RET kinase alterations in targeted cancer therapy

Abstract

The rearranged during transfection (RET) gene encodes a protein tyrosine kinase. RET alterations by point mutations and gene fusions were found in diverse cancers. RET fusions allow abnormal expression and activation of the oncogenic kinase, whereas only a few of RET point mutations found in human cancers are known oncogenic drivers. Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors (TKIs) with RET inhibitor activity. These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations. Recently, two potent and selective RET TKIs, pralsetinib (BLU-667) and selpercatinib (LOXO-292), were developed. High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials, demonstrating the RET dependence in human cancers harboring these RET lesions. Pralsetinib and selpercatinib were effective in inhibiting RET^V804L/M gatekeeper mutants. However, adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RET^G810 residue have been found, pointing to the need for the development of the next-generation of RET TKIs.

Keywords

Rearranged during transfection / protein tyrosine kinase inhibitor / mutation / gene fusion / targeted therapy / acquired resistance

References

[1] Mulligan LM.RET revisited: expanding the oncogenic portfolio..Nat Rev Cancer2014;14:173-86

[2] Roskoski R Jr.Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers..Pharmacol Res2018;128:1-17

[3] Li J,Chen YJ,Liou J.Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands..Elife2019;8: PMCID:PMC6760901

[4] Drilon A,Lai GGY.Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes..Nat Rev Clin Oncol2018;15:151-67

[5] Krampitz GW.RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma..Cancer2014;120:1920-31

[6] Santoro M,Romano A,Dathan NA.Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B..Science1995;267:381-3

[7] Grieco M,Berlingieri MT,Donghi R.PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas..Cell1990;60:557-63

[8] Ju YS,Shin JY,Bleazard T.A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing..Genome Res2012;22:436-45 PMCID:PMC3290779

[9] Kohno T,Totoki Y,Hiramoto M.KIF5B-RET fusions in lung adenocarcinoma..Nat Med2012;18:375-7 PMCID:PMC6430196

[10] Lipson D,Yelensky R,Parker A.Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies..Nat Med2012;18:382-4 PMCID:PMC3916180

[11] Takeuchi K,Togashi Y,Sakata S.RET, ROS1 and ALK fusions in lung cancer..Nat Med2012;18:378-81

[12] Gao J,Dogrusoz U,Gross B.Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal..Sci Signal2013;6:pl1 PMCID:PMC4160307

[13] Kato S,Marchlik E,Carter JL.RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients..Clin Cancer Res2017;23:1988-97

[14] Rich TA,Chae YK,Iams WT.Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations..Clin Cancer Res2019;25:5832-42 PMCID:PMC6774853

[15] Drilon A,Arcila M,Ni A.Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial..Lancet Oncol2016;17:1653-60 PMCID:PMC5143197

[16] Lee SH,Ahn MJ,Sun JM.Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial..Ann Oncol2017;28:292-7

[17] Yoh K,Satouchi M,Yamamoto N.Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial..Lancet Respir Med2017;5:42-50

[18] Subbiah V,Rahal R,Kim JL.Precision Targeted Therapy with BLU-667 for RET-Driven Cancers..Cancer Discov2018;8:836-49

[19] Subbiah V,Tuch BB,Busaidy NL.Selective RET kinase inhibition for patients with RET-altered cancers..Ann Oncol2018;29:1869-76 PMCID:PMC6096733

[20] Gainor JF,Curijgliano G,Kim CSB.Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC)..ASCO Annual Meeting2019;Abstract 9008

[21] Drilon A,Wirth L,Gautschi O.PL02.08: registrational results of LIBRETTO-001: a Phase 1/2 Trial of LOXO-292 in patients with RET fusion-positive lung cancers..J Thorac Oncol2019;14:S6-S7

[22] Solomon BJ,Lin JJ,Hollizeck S.RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies..J Thorac Oncol2020;15:541-9

[23] Wells SA Jr,Robinson BG.Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update..J Clin Endocrinol Metab2013;98:3149-64 PMCID:PMC5399478

[24] Plaza-Menacho I,Goodman K,Borg A.Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans..Mol Cell2014;53:738-51 PMCID:PMC3988870

[25] Goodman KM,Beuron F,Nawrotek A.RET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association..Cell Rep2014;8:1894-904

[26] Asai N,Matsuyama M.Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations..Mol Cell Biol1995;15:1613-9 PMCID:PMC230385

[27] Terzyan SS,Liu X,Teng P.Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib..J Biol Chem2019;294:10428-37 PMCID:PMC6615680

[28] Cerami E,Dogrusoz U,Sumer SO.The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data..Cancer Discov2012;2:401-4 PMCID:PMC3956037

[29] Levinson S.Drosophila cancer models identify functional differences between ret fusions..Cell Rep2016;16:3052-61 PMCID:PMC5858711

[30] Das TK.KIF5B-RET oncoprotein signals through a multi-kinase signaling hub..Cell Rep2017;20:2368-83 PMCID:PMC5590648

[31] Gainor JF.Novel targets in non-small cell lung cancer: ROS1 and RET fusions..Oncologist2013;18:865-75 PMCID:PMC3720641

[32] Tsuta K,Yoshida A,Asamura H.RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis..Br J Cancer2014;110:1571-8 PMCID:PMC3960615

[33] Wang R,Pan Y,Ye T.RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer..J Clin Oncol2012;30:4352-9

[34] Mizukami T,Shimada Y,Tsuta K.Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma..J Thorac Oncol2014;9:622-30

[35] Paratala BS,Williams CB,Petrosky W.RET rearrangements are actionable alterations in breast cancer..Nat Commun2018;9:4821 PMCID:PMC6240119

[36] Nigro CL,Ceccherini I.RET in breast cancer: pathogenic implications and mechanisms of drug resistance..Cancer Drug Resist2019;2:1136-52

[37] Drilon A,Hasanovic A,Lipson D.Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas..Cancer Discov2013;3:630-5 PMCID:PMC4160032

[38] Gautschi O,Filleron T,Carbone DP.Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry..J Clin Oncol2017;35:1403-10 PMCID:PMC5559893

[39] Hida T,Reckamp KL,Sachdev P.A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma..Lung Cancer2019;138:124-30

[40] Drilon A,Filleron T,Milia J.Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers..J Thorac Oncol2018;13:1595-601 PMCID:PMC6434708

[41] James J,Armstrong RC,Jones-Bolin S.CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity..Mol Cancer Ther2012;11:930-41

[42] Li GG,Joseph J,Hayashi T.Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations..Clin Cancer Res2017;23:2981-90 PMCID:PMC5477238

[43] Drilon A,Patel MR,Wang D.A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105..Cancer Discov2019;9:384-95 PMCID:PMC6397691

[44] Brandhuber BJ,Tuch B,Bouhana K.The development of a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers..Eur J Cancer2016;69:S144

[45] Taylor MH,Hu MI,Lopes G.Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers..J Clin Oncol2019;37:Abstract 6018

[46] Shah NP,Nagar B,Paquette RL.Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia..Cancer Cell2002;2:117-25

[47] Hochhaus A,Corbin AS,Muller MC.Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy..Leukemia2002;16:2190-6

[48] Gorre ME,Ellwood K,Paquette R.Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification..Science2001;293:876-80

[49] Riely GJ.EGFR: The paradigm of an oncogene-driven lung cancer..Clin Cancer Res2015;21:2221-6 PMCID:PMC4435716

[50] Katayama R,Khan TM,Solomon BJ.Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers..Sci Transl Med2012;4:120ra17 PMCID:PMC3385512

[51] Katayama R,Shaw AT.Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine..Clin Cancer Res2015;21:2227-35 PMCID:PMC4435823

[52] Gainor JF.Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer..J Clin Oncol2013;31:3987-96 PMCID:PMC3805932

[53] Awad MM,McTigue M,Deng YL.Acquired resistance to crizotinib from a mutation in CD74-ROS1..N Engl J Med2013;368:2395-401 PMCID:PMC3878821

[54] Carlomagno F,Anaganti S,Fusco A.Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors..Oncogene2004;23:6056-63

[55] Carlomagno F,Anaganti S,Kjaer S.Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474..Endocr Relat Cancer2009;16:233-41

[56] Huang Q,Luetteke N,Afzal R.Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma..Mol Cancer Ther2016;15:2521-9 PMCID:PMC5289739

[57] Liu X,Mooers BHM,Wu J.Drug resistance profiles of mutations in the RET kinase domain..Br J Pharmacol2018;175:3504-15 PMCID:PMC6086982

[58] Nakaoku T,Araki M,Chauhan R.A secondary RET mutation in the activation loop conferring resistance to vandetanib..Nat Commun2018;9:625 PMCID:PMC5809600

[59] Dagogo-Jack I,Lin JJ,Ferris L.Emergence of a RET V804M Gatekeeper mutation during treatment with Vandetanib in RET-rearranged NSCLC..J Thorac Oncol2018;13:e226-e7

[60] Andrews SW,Blake JF,Cook A.Substituted pyrazol[1,5-A]pyridine compounds as RET kinase inhibitors..WO2018/071447 A12017;

[61] Ou SI,Schrock AB,Zhu VW.Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib..Lung Cancer2017;108:228-31

[62] Yang Z,Ou Q,Jiang T.Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients..Clin Cancer Res2018;24:3097-107

[63] Gainor JF,Yoda S,Leshchiner I.Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer..Cancer Discov2016;6:1118-33 PMCID:PMC5050111

[64] Zhang S,Squillace R,Zhou T.The potent ALK inhibitor Brigatinib (AP26113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models..Clin Cancer Res2016;22:5527-38

[65] Gainor JF,Yoda S,Friboulet L.Patterns of metastatic spread and mechanisms of resistance to Crizotinib in ROS1-positive non-small-cell lung cancer..JCO Precis Oncol2017;2017: PMCID:PMC5766287

[66] Fuse MJ,Oh-Hara T,Fujita N.Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers..Mol Cancer Ther2017;16:2130-43

[67] Shen T,Liu X,Wu J.Structural insight into sensitivity and resistance of RET mutants to selpercatinib (LOXO-292). Sixth AACR-IASLC International Joint Conference:.Lung Cancer Translational Science from the Bench to the Clinic2020;Abstract:B18

[68] Kohno T,Nakaoku T.REToma: a cancer subtype with a shared driver oncogene..Carcinogenesis2019;Epub ahead of print. doi: 10.1093/carcin/bgz184

[69] Drilon A,Cho BC,Lee J.Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations..Cancer Discov2018;8:1227-36