FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

Abstract

In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.

Keywords

Bladder Cancer / Erdafitinib / FGFR inhibition / FGFR3 mutations / Resistance to Erdafitinib / Tumor Microenvironment

References

[1] Tran L, Xiao J-F, Agarwal N, Duex JE, Theodorescu D. Advances in bladder cancer biology and therapy. Nat Rev Cancer. 2021; 21: 104-21.

[2] Dyrskjøt L, Hansel DE, Efstathiou JA, Knowles MA, Galsky MD, Teoh J, et al. Bladder cancer. Nat Rev Dis Prim. 2023; 9: 58.

[3] Ascione CM, Napolitano F, Esposito D, Servetto A, Belli S, Santaniello A, et al. Role of FGFR3 in bladder cancer: Treatment landscape and future challenges. Cancer Treat Rev. 2023; 115: 102530.

[4] The American Cancer Society medical and editorial content team. Can bladder cancer be found early? Am Cancer Soc. 2016: 1-25.

[5] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69: 7-34.

[6] Williams SB, Howard LE, Foster ML, Klaassen Z, Sieluk J, De Hoedt AM, et al. Estimated Costs and Long-term Outcomes of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer Treated With Bacillus Calmette-Guérin in the Veterans Affairs Health System. JAMA Netw Open. 2021; 4: e213800.

[7] Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X. et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999; 23: 18-20.

[8] Bernard-Pierrot I, Brams A, Dunois-Lardé C, Caillault A, Diez de Medina SG, Cappellen D, et al. Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis. 2006; 27: 740-7.

[9] Tomlinson DC, Hurst CD, Knowles MA. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 2007; 26: 5889-99.

[10] Williams S V, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet. 2013; 22: 795-803.

[11] Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014; 507: 315-22.

[12] Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020; 77: 420-33.

[13] Pal SK, Rosenberg JE, Hoffman-Censits JH. Berger R, Quinn DI, Galsky MD, et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. Cancer Discov. 2018; 8: 812-21.

[14] Loriot Y, Necchi A, Park SH, Garcia-Donas J. Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019; 381: 338-48.

[15] Volkmer J-P, Sahoo D, Chin RK, Ho PL, Tang C, Kurtova A V, et al. Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A. 2012; 109: 2078-83.

[16] Hedegaard J, Lamy P, Nordentoft I, Algaba F, Høyer S, Ulhøi BP, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell. 2016; 30: 27-42.

[17] Komura K, Hirosuna K, Tokushige S, Tsujino T, Nishimura K, Ishida M, et al. The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer. Mol Cancer. 2023; 22: 185.

[18] Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet. 2013; 45: 1459-63.

[19] Webster MK, Donoghue DJ. FGFR activation in skeletal disorders: too much of a good thing. Trends Genet. 1997; 13: 178-82.

[20] Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996; 13: 233-7.

[21] Vaeyens F, Hetzel J-P, Mernberger M, Eggermont C, Olsen C, Maes K, et al. Variant-Specific Landscape of Mutual Exclusivity Among BRAF, EGFR, and KRAS Oncogenes in Human Cancer. MedRxiv. 2023:23297089.

[22] Shi M-J, Meng X-Y, Lamy P, Banday AR, Yang J, Moreno-Vega A. et al. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer. Eur Urol. 2019; 76: 9-13.

[23] Guercio BJ, Sarfaty M, Teo MY, Ratna N, Duzgol C, Funt SA, et al. Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience. Clin Cancer Res an Off J Am Assoc Cancer Res. 2023; 29: 4586-95.

[24] di Martino E, L’Hôte CG, Kennedy W, Tomlinson DC, Knowles MA. Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type-and mutation-specific manner. Oncogene. 2009; 28: 4306-16.

[25] Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007; 213: 91-8.

[26] Shi M-J, Fontugne J, Moreno-Vega A. Meng X-Y, Groeneveld C, Dufour F, et al. FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias. Eur Urol. 2023; 83: 70-81.

[27] Ahmad I, Singh LB, Foth M, Morris C-A, Taketo MM, Wu X-R, et al. K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladder. Dis Model Mech. 2011; 4: 548-55.

[28] Krook MA, Reeser JW, Ernst G, Barker H, Wilberding M, Li G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2021; 124: 880-92.

[29] Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther. 2020; 5: 181.

[30] Subbiah V, Verstovsek S. Clinical development and management of adverse events associated with FGFR inhibitors. Cell Reports Med. 2023; 4: 101204.

[31] Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022; 23: 248-58.

[32] Hanna K. Erdafitinib’s Road to Approval and Use in Urothelial Carcinoma. Oncology (Williston Park). 2023; 37: 260-1.

[33] Pant S, Schuler M, Iyer G, Witt O, Doi T, Qin S, et al. Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. Lancet Oncol. 2023; 24: 925-35.

[34] Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023; 389: 1961-71.

[35] Catto JWF, Tran B, Rouprêt M, Gschwend JE, Loriot Y, Nishiyama H, et al. Erdafitinib in BCG-treated high-risk non-muscle invasive bladder cancer. Ann Oncol Off J Eur Soc Med Oncol. 2023.

[36] Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol Off J Eur Soc Med Oncol. 2024; 35: 107-17.

[37] Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol Off J Eur Soc Med Oncol. 2024; 35: 107-17.

[38] Catto JWF, Tran B, Rouprêt M, Gschwend JE, Loriot Y, Nishiyama H, et al. Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer. Ann Oncol Off J Eur Soc Med Oncol. 2024; 35: 98-106.

[39] Vilaseca A, Jayram G, Raventos C, Shore ND, Zainfeld D, Kang TW, et al. LBA104 First safety and efficacy results of the TAR-210 erdafitinib (erda) intravesical delivery system in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) with select FGFR alterations (alt). Ann Oncol. 2023; 34: S1343.

[40] Kommalapati A, Tella SH, Borad M, Javle M, Mahipal A. FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice. Cancers (Basel). 2021; 13.

[41] Necchi A, Pouessel D, Leibowitz R, Gupta S, Fléchon A, García-Donas J, et al. Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201. Ann Oncol Off J Eur Soc Med Oncol. 2024; 35: 200-10.

[42] Rodón J, Damian S, Furqan M, García-Donas J, Imai H, Italiano A, et al. Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial. Nat Med. 2024.

[43] Zhao D, Long X, Zhou J, Wang J. Pharmacovigilance Study of Infigratinib: A Safety Analysis of the FDA Adverse Event Reporting System. Drugs R D. 2023; 23: 403-9.

[44] Meric-Bernstam F, Hollebecque A, Furuse J, Oh D-Y, Bridgewater JA, Shimura M, et al. Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1-4 Inhibitor: Pooled Safety Analysis of 469 Patients. Clin Cancer Res an Off J Am Assoc Cancer Res. 2024; 30: 1466-77.

[45] Javle M, King G, Spencer K, Borad MJ. Futibatinib, an Irreversible FGFR1-4 Inhibitor for the Treatment of FGFR-Aberrant Tumors. Oncologist. 2023; 28: 928-43.

[46] Vilaseca A, Jayram G, Raventos C, Shore ND, Zainfeld D, Kang TW, et al. LBA104 First safety and efficacy results of the TAR-210 erdafitinib (erda) intravesical delivery system in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) with select FGFR alterations (alt). Ann Oncol. 2023; 34: S1343.

[47] Goyal R, Jialal I. Hyperphosphatemia. Treasure Island (FL): 2024.

[48] Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R. et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020; 21: 671-84.

[49] Bahleda R, Italiano A, Hierro C, Mita A, Cervantes A, Chan N, et al. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblas. Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Clin Cancer Res an Off J Am Assoc Cancer Res. 2019; 25: 4888-97.

[50] Dosne A-G, Valade E, Stuyckens K, De Porre P, Avadhani A, O’Hagan A, et al. Erdafitinib’s effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer. CPT Pharmacometrics Syst Pharmacol. 2022; 11: 569-80.

[51] Martínez-Torrecuadrada J, Cifuentes G, López-Serra P, Saenz P, Martínez A, Casal JI. Targeting the Extracellular Domain of Fibroblast Growth Factor Receptor 3 with Human Single-Chain Fv Antibodies Inhibits Bladder Carcinoma Cell Line Proliferation. Clin Cancer Res. 2005; 11: 6280-90.

[52] Siefker-Radtke AO, Lugowska I, Tupikowski K, Andric ZG, Rezazadeh Kalebasty A, Curigliano G, et al. 917P -Clinical activity of vofatamab (V), an FGFR3 selective antibody in combination with pembrolizumab (P) in metastatic urothelial carcinoma (mUC), updated interim analysis of FIERCE-22. Ann Oncol. 2019; 30: v365.

[53] Mellado B, Castellano DE, Pang S, Urun Y, Park SH, Vaishampayan UN, et al. Interim analysis of the fierce-21 phase 2 (P2) study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC). J Clin Oncol. 2019; 37: 4547.

[54] Bellmunt J, Picus J, Kohli M, Arriaga YE, Milowsky MI, Currie G, et al. FIERCE-21: Phase 1b/2 study of docetaxel + b-701, a selective inhibitor of FGFR3, in relapsed or refractory (R/R) metastatic urothelial carcinoma (mUCC). J Clin Oncol. 2018; 36: 4534.

[55] Qing J, Du X, Chen Y, Chan P, Li H, Wu P, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest. 2009; 119: 1216-29.

[56] Wang X, Ye C-H, Li E-M. Xu L-Y, Lin W-Q. Chen G-H. Discovery of octahydropyrrolo [3, 2-b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high-throughput virtual screening. J Cell Biochem. 2023; 124: 221-38.

[57] Ornitz DM, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015; 4: 215-66.

[58] Jaye M, Howk R, Burgess W, Ricca GA, Chiu IM, Ravera MW, et al. Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization. Science. 1986; 233: 541-5.

[59] Karl K, Del Piccolo N, Light T, Roy T, Dudeja P, Ursachi V-C, et al. Ligand bias underlies differential signaling of multiple FGFs via FGFR1 2023.

[60] Keegan K, Rooke L, Hayman M, Spurr NK. The fibroblast growth factor receptor 3 gene (FGFR3) is assigned to human chromosome 4. Cytogenet Cell Genet. 1993; 62: 172-5.

[61] Sarabipour S, Hristova K. Mechanism of FGF receptor dimerization and activation. Nat Commun. 2016; 7: 10262.

[62] Hartl I, Brumovska V, Striedner Y, Yasari A, Schütz GJ, Sevcsik E, et al. Measurement of FGFR3 signaling at the cell membrane via total internal reflection fluorescence microscopy to compare the activation of FGFR3 mutants. J Biol Chem. 2023; 299: 102832.

[63] Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Rev. 2015; 34: 479-96.

[64] Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer. 2017; 17: 318-32.

[65] Dienstmann R, Rodon J, Prat A, Perez-Garcia J. Adamo B, Felip E, et al. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann Oncol Off J Eur Soc Med Oncol. 2014; 25: 552-63.

[66] Haugsten EM, Wiedlocha A, Olsnes S, Wesche J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res. 2010; 8: 1439-52.

[67] Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011; 437: 199-213.

[68] Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in Cancer: Analysis of 4, 853 Tumors by Next-Generation Sequencing. Clin Cancer Res an Off J Am Assoc Cancer Res. 2016; 22: 259-67.

[69] Touat M, Ileana E, Postel-Vinay S. André F, Soria J-C. Targeting FGFR Signaling in Cancer. Clin Cancer Res an Off J Am Assoc Cancer Res. 2015; 21: 2684-94.

[70] Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019; 16: 105-22.

[71] Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, et al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017; 8: 16052-74.

[72] Porta R, Borea R, Coelho A, Khan S, Araújo A, Reclusa P, et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Crit Rev Oncol Hematol. 2017; 113: 256-67.

[73] Rosty C, Aubriot M-H, Cappellen D, Bourdin J, Cartier I, Thiery JP, et al. Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Mol Cancer. 2005; 4: 15.

[74] Yoshimoto Y, Sasaki Y, Murata K, Noda S-E, Miyasaka Y, Hamamoto J, et al. Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy. Gynecol Oncol. 2020; 159: 546-53.

[75] Gött H, Uhl E. FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma. Int J Mol Sci. 2022; 23.

[76] Benard B, Christofferson A, Legendre C, Aldrich J, Nasser S, Yesil J, et al. FGFR3 Mutations Are an Adverse Prognostic Factor in Patients with t(4;14)(p16;q32) Multiple Myeloma: An Mmrf Commpass Analysis. Blood. 2017; 130: 3027. https://doi.org/10.1182/blood.V130.Suppl_1.3027.3027

[77] Ermakov MS, Kashofer K, Regauer S. Different Mutational Landscapes in Human Papillomavirus-Induced and Human Papillomavirus-Independent Invasive Penile Squamous Cell Cancers. Mod Pathol an Off J United States Can Acad Pathol Inc. 2023; 36: 100250.

[78] Czyz M. Fibroblast Growth Factor Receptor Signaling in Skin Cancers. Cells. 2019; 8.

[79] Castillo P, Marginet M, Jares P, García M, Gonzalvo E, Arance A, et al. Implementation of an NGS panel for clinical practice in paraffin-embedded tissue samples from locally advanced and metastatic melanoma patients. Explor Target Anti-Tumor Ther. 2020; 1: 101-8.

[80] Aparicio T, Svrcek M, Henriques J, Afchain P, Lièvre A, Tougeron D, et al. Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort. Int J Cancer. 2021; 148: 1731-42.

[81] Suster D, Mackinnon AC, Ronen N, Mejbel HA, Harada S, Suster S. Non-Small Cell Lung Carcinoma With Clear Cell Features and FGFR3::TACC3 Gene Rearrangement : Clinicopathologic and Next Generation Sequencing Study of 7 Cases. Am J Surg Pathol. 2024; 48: 284-91.

[82] Li J, Hu K, Huang J, Zhou L, Yan Y, Xu Z. Insights of fibroblast growth factor receptor 3 aberrations in pan-cancer and their roles in potential clinical treatment. Aging (Albany NY). 2021; 13: 16541-66.

[83] Hafner C, Hartmann A, van Oers JMM, Stoehr R, Zwarthoff EC, Hofstaedter F, et al. FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization. Mod Pathol an Off J United States Can Acad Pathol Inc. 2007; 20: 895-903.

[84] Hafner C, van Oers JMM, Hartmann A, Landthaler M, Stoehr R, Blaszyk H, et al. High frequency of FGFR3 mutations in adenoid seborrheic keratoses. J Invest Dermatol. 2006; 126: 2404-7.

[85] Wang X, Qi H, Wang Q, Zhu Y, Wang X, Jin M, et al. FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia. Autophagy. 2015; 11: 1998-2013.

[86] Smith LB, Belanger JM, Oberbauer AM. Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes. J Anim Sci Biotechnol. 2012; 3: 39.

[87] Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999; 84: 476-80.

[88] Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000; 67: 1411-21.

[89] Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet. 1995; 56: 368-73.

[90] Aviezer D, Golembo M, Yayon A. Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia–genetic short limbed dwarfism. Curr Drug Targets. 2003; 4: 353-65.

[91] Aikawa T, Segre G V, Lee K. Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. J Biol Chem. 2001; 276: 29347-52.

[92] Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat. 2012; 33: 29-41.

[93] Xie Y, Zinkle A, Chen L, Mohammadi M. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat Rev Rheumatol. 2020; 16: 547-64.

[94] Kunova Bosakova M, Varecha M, Hampl M, Duran I, Nita A, Buchtova M, et al. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum Mol Genet. 2018; 27: 1093-105.

[95] Martin L, Kaci N, Estibals V, Goudin N, Garfa-Traore M. Benoist-Lasselin C, et al. Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia. Hum Mol Genet. 2018; 27: 1-13.

[96] Iwata T, Li CL, Deng CX, Francomano CA. Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Hum Mol Genet. 2001; 10: 1255-64.

[97] Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka P V, et al. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest. 1999; 104: 1517-25.

[98] Wen X, Li X, Tang Y, Tang J, Zhou S, Xie Y, et al. Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis. J Biol Chem. 2016; 291: 24912-21.

[99] Yao X, Zhang J, Jing X, Ye Y, Guo J, Sun K, et al. Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission. Pharmacol Res. 2019; 139: 314-24.

[100] Ota S, Tonou-Fujimori N. Yamasu K. The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors. Mech Dev. 2009; 126: 1-17.

[101] Sun X, Zhang R, Chen H, Du X, Chen S, Huang J, et al. Fgfr3 mutation disrupts chondrogenesis and bone ossification in zebrafish model mimicking CATSHL syndrome partially via enhanced Wnt/β-catenin signaling. Theranostics. 2020; 10: 7111-30.

[102] Toydemir RM, Brassington AE, Bayrak-Toydemir P. Krakowiak PA, Jorde LB, Whitby FG, et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet. 2006; 79: 935-41.

[103] Jang J-H, Shin K-H, Park Y-J. Lee RJ, McKeehan WL, Park J-G. Novel Transcripts of Fibroblast Growth Factor Receptor 3 Reveal Aberrant Splicing and Activation of Cryptic Splice Sequences in Colorectal Cancer1. Cancer Res. 2000; 60: 4049-52.

[104] Fromme JE, Schmitz K, Wachter A, Grzelinski M, Zielinski D, Koppel C, et al. FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis. Oncotarget. 2018; 9: 32204-18.

[105] Jin Z, Feng H, Liang J, Jing X, Zhao Q, Zhan L, et al. FGFR3(△7-9) promotes tumor progression via the phosphorylation and destabilization of ten-eleven translocation-2 in human hepatocellular carcinoma. Cell Death Dis. 2020; 11: 903.

[106] Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B, et al. FGFR3 has tumor suppressor properties in cells with epithelial phenotype. Mol Cancer. 2013; 12: 83.

[107] Zheng J, Zhang W, Li L, He Y, Wei Y, Dang Y, et al. Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review. Front Chem. 2022; 10: 860985.

[108] Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 2017; 9.

[109] Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers (Basel). 2019; 11.

[110] Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol. 2022; 85: 123-54.

[111] Krejci P, Salazar L, Goodridge HS, Kashiwada TA, Schibler MJ, Jelinkova P, et al. STAT1 and STAT3 do not participate in FGF-mediated growth arrest in chondrocytes. J Cell Sci. 2008; 121: 272-81.

[112] Nguyen HB, Estacion M, Gargus JJ. Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF-induced calcium signals in human diploid fibroblasts. Hum Mol Genet. 1997; 6: 681-8.

[113] Koike M, Yamanaka Y, Inoue M, Tanaka H, Nishimura R, Seino Y. Insulin-like growth factor-1 rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase and MAPK. J Bone Miner Res Off J Am Soc Bone Miner Res. 2003; 18: 2043-51.

[114] de Miranda MC, Rodrigues MA, de Angelis Campos AC, Faria JAQA, Kunrath-Lima M. Mignery GA, et al. Epidermal growth factor (EGF) triggers nuclear calcium signaling through the intranuclear phospholipase Cδ-4 (PLCδ4). J Biol Chem. 2019; 294: 16650-62.

[115] Eggermont C, Giron P, Noeparast M, Vandenplas H, Aza-Blanc P. Gutierrez GJ, et al. The EGFR-STYK1-FGF1 axis sustains functional drug tolerance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer. Cell Death Dis. 2022; 13: 611.

[116] Giron P, Eggermont C, Noeparast A, Vandenplas H, Teugels E, Forsyth R, et al. Targeting USP13-mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non-small cell lung cancer. Int J Cancer. 2020; 148: 2579-93.

[117] Umelo I, Noeparast A, Chen G, Renard M, Geers C, Vansteenkiste J, et al. Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer. Oncotarget. 2016; 7: 3068-83.

[118] Ren Y, Cheng L, Rong Z, Li Z, Li Y, Zhang X, et al. hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation. Cell Signal. 2008; 20: 518-33.

[119] Pinilla-Macua I, Sorkin A. Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes. Mol Biol Cell. 2023; 34: ar134.

[120] Reich A, Sapir A, Shilo B. Sprouty is a general inhibitor of receptor tyrosine kinase signaling. Development. 1999; 126: 4139-47.

[121] Unni AM, Harbourne B, Oh MH, Wild S, Ferrarone JR, Lockwood WW, et al. Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells. Elife. 2018; 7: 1-24.

[122] Giron P, Eggermont C, Noeparast A, Teugels E, Gutierrez G, De Grève J. The deubiquitinase USP13 as a novel therapeutic co-target in EGFR mutant non-small cell lung cancer, 2018.

[123] Mahe M, Dufour F, Neyret-Kahn H. Moreno-Vega A, Beraud C, Shi M, et al. An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers. EMBO Mol Med. 2018; 10: e8163.

[124] Weickhardt AJ, Lau DK, Hodgson-Garms M. Lavis A, Jenkins LJ, Vukelic N, et al. Dual targeting of FGFR3 and ERBB3 enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer. BMC Cancer. 2022; 22: 478.

[125] Hosni S, Kilian V, Klümper N, Gabbia D, Sieckmann K, Corvino D, et al. Adipocyte precursor-derived NRG1 promotes resistance to FGFR inhibition in urothelial carcinoma. Cancer Res. 2024.

[126] Herrera-Abreu MT, Pearson A, Campbell J, Shnyder SD, Knowles MA, Ashworth A, et al. Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discov. 2013; 3: 1058-71.

[127] Wang L, Šuštić T, Leite de Oliveira R, Lieftink C, Halonen P, van de Ven M, et al. A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma. Eur Urol. 2017; 71: 858-62.

[128] Nössing C, Herek P, Shariat SF, Berger W, Englinger B. Advances in preclinical assessment of therapeutic targets for bladder cancer precision medicine. Curr Opin Urol. 2024; 34: 251-7.

[129] Szklener K, Chmiel P, Michalski A, Mańdziuk S. New Directions and Challenges in Targeted Therapies of Advanced Bladder Cancer: The Role of FGFR Inhibitors. Cancers (Basel). 2022; 14.

[130] Rose TL, Weir WH, Mayhew GM, Shibata Y, Eulitt P, Uronis JM, et al. Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience. Br J Cancer. 2021; 125: 1251-60.

[131] Wang L, Saci A, Szabo PM, Chasalow SD, Castillo-Martin M. Domingo-Domenech J, et al. EMT-and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat Commun. 2018; 9: 3503.

[132] Ouyang Y, Ou Z, Zhong W, Yang J, Fu S, Ouyang N, et al. FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation. Cancer Res. 2023.

[133] Okato A, Utsumi T, Ranieri M, Zheng X, Zhou M, Pereira LD, et al. FGFR inhibition augments anti-PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression. J Clin Invest. 2024; 134.

[134] Jing W, Wang G, Cui Z, Xiong G, Jiang X, Li Y, et al. FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell-Mediated Bladder Cancer Immune Surveillance. Cancer Res. 2022; 82: 114-29.

[135] Trujillo JA, Sweis RF, Bao R, Luke JJ. T Cell-Inflamed versus Non-T Cell-Inflamed Tumors: A Conceptual Framework for Cancer Immunotherapy Drug Development and Combination Therapy Selection. Cancer Immunol Res. 2018; 6: 990-1000.

[136] Aksoylar H-I, Boussiotis VA. PD-1+ Treg cells: a foe in cancer immunotherapy? Nat Immunol. 2020; 21: 1311-2.

[137] Song Y, Peng Y, Qin C, Wang Y, Yang W, Du Y, et al. Fibroblast growth factor receptor 3 mutation attenuates response to immune checkpoint blockade in metastatic urothelial carcinoma by driving immunosuppressive microenvironment. J Immunother Cancer. 2023; 11.

[138] Robertson AG, Meghani K, Cooley LF, McLaughlin KA, Fall LA, Yu Y, et al. Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer. Nat Commun. 2023; 14: 2126.

[139] Xu P-H, Chen S, Wang Y, Jin S, Wang J, Ye D, et al. FGFR3 mutation characterization identifies prognostic and immune-related gene signatures in bladder cancer. Comput Biol Med. 2023; 162: 106976.

[140] Wang L, Gong Y, Saci A, Szabo PM, Martini A, Necchi A, et al. Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer. Eur Urol. 2019; 76: 599-603.

[141] Li X, Li Y, Liu B, Chen L, Lyu F, Zhang P, et al. P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer. FASEB J Off Publ Fed Am Soc Exp Biol. 2023; 37: e22840.

[142] Pettitt GA, Hurst CD, Khan Z, McPherson HR, Dunning MC, Alder O, et al. Development of resistance to FGFR inhibition in urothelial carcinoma via multiple pathways in vitro. J Pathol. 2023; 259: 220-32.

[143] Facchinetti F, Hollebecque A, Braye F, Vasseur D, Pradat Y, Bahleda R, et al. Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer. Cancer Discov. 2023; 13: 1998-2011.

[144] Wang Z, Muthusamy V, Petrylak DP, Anderson KS. Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy. Npj Precis Oncol. 2023; 7: 70.

[145] Lang H, Béraud C, Cabel L, Fontugne J, Lassalle M, Krucker C, et al. Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies. Front Oncol. 2022; 12: 930731.

[146] Stiewe T, Haran TE. How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance. Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother. 2018; 38: 27-43.

[147] Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelletti M, Rogers A, et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene. 2010; 29: 2346-56.

[148] Kikuchi A, Suzuki T, Nakazawa T, Iizuka M, Nakayama A, Ozawa T, et al. ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance. Cancer Sci. 2017; 108: 236-42.

[149] Qin Z-Q, Li Q-G, Yi H, Lu S-S, Huang W, Rong Z-X, et al. Heterozygous p53-R280T Mutation Enhances the Oncogenicity of NPC Cells Through Activating PI3K-Akt Signaling Pathway. Front Oncol. 2020; 10: 104.

[150] Levine AJ. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 2020; 20: 471-80.

[151] Bargonetti J, Prives C. Gain-of-function mutant p53: history and speculation. J Mol Cell Biol. 2019; 11: 605-9.

[152] Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov A V, et al. A dominant-negative effect drives selection of <em>TP53</em> missense mutations in myeloid malignancies. Science (80-). 2019; 365: 599 LP–604.

[153] Kotler E, Shani O, Goldfeld G, Lotan-Pompan M. Tarcic O, Gershoni A, et al. A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. Mol Cell. 2018; 71: 178-190.e8.

[154] Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022; 13: 1-14.

[155] Maiorano BA, Catalano M, Maiello E, Roviello G. Enfortumab vedotin in metastatic urothelial carcinoma: the solution EVentually? Front Oncol. 2023; 13: 1254906.

[156] Santini D, Banna GL, Buti S, Isella L, Stellato M, Roberto M, et al. Navigating the Rapidly Evolving Advanced Urothelial Carcinoma Treatment Landscape: Insights from Italian Experts. Curr Oncol Rep. 2023; 25: 1345-62.

[157] Jain RK, Heiligh J, Kim Y, Piekarz R, Pelosof LC, Yang Y (Aaron), et al. Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs). J Clin Oncol. 2024; 42: 625.

[158] Bock C, Lengauer T. Managing drug resistance in cancer: lessons from HIV therapy. Nat Rev Cancer. 2012; 12: 494-501.

[159] Langreth R, Waldholz M. New era of personalized medicine: targeting drugs for each unique genetic profile. Oncologist. 1999; 4: 426-7.

[160] Dankner M, Rose AANN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: New rational therapeutic strategies for actionable mutations. Oncogene. 2018; 37: 3183-99.

[161] Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res an Off J Am Assoc Cancer Res. 2009; 15: 3484-94.

[162] Moore S, Wheatley-Price P. EGFR Combination Therapy Should Become the New Standard First-Line Treatment in Advanced EGFR-Mutant NSCLC. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2021; 16: 1788-92.

[163] Settleman J, Neto JMF, Bernards R. Thinking Differently about Cancer Treatment Regimens. Cancer Discov. 2021; 11: 1016-23.

[164] Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, et al. An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer. Nat Med. 2017; 23: 929-37.

[165] Kaelin WG. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med. 2009; 1: 99.

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