Network rewiring, adaptive resistance and combating strategies in breast cancer

Abstract

Resistance to targeted anti-cancer drugs is a complex phenomenon and a major challenge in cancer treatment. It is becoming increasingly evident that a form of acquired drug resistance known as “adaptive resistance” is a common cause of treatment failure and patient relapse in many cancers. Unlike classical resistance mechanisms that are acquired via genomic alterations, adaptive resistance is instead driven by non-genomic changes involving rapid and dynamic rewiring of signalling and/or transcriptional networks following therapy, enabled by complex pathway crosstalk and feedback regulation. Such network rewiring allows tumour cells to adapt to the drug treatment, circumvent the initial drug challenge and continue to survive in the presence of the drug. Despite its great clinical importance, adaptive resistance remains largely under-studied and poorly defined. This review is focused on recent findings which provide new insights into the mechanisms underlying adaptive resistance in breast cancer, highlighting how breast tumour cells rewire intracellular signalling pathways to overcome the stress of initial targeted therapy. In particular, we investigate adaptive resistance to targeted inhibition of two major oncogenic signalling axes frequently dysregulated in breast cancer, the PI3K-AKT-mTOR and RAS-MAPK signalling pathways; and discuss potential combination treatment strategies that overcome such resistance. In addition, we highlight application of quantitative and computational modelling as a novel integrative and powerful approach to gain network-level understanding of network rewiring, and rationally identify and prioritise effective drug combinations.

Keywords

Network rewiring / adaptive resistance / PI3K signalling / MAPK signalling / breast cancer / mathematical modelling / systems analysis

References

[1] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[2] Rueff J.Cancer drug resistance: a brief overview from a genetic viewpoint..Methods Mol Biol2016;1395:1-18

[3] Housman G,Heerboth S,Longacre M.Drug resistance in cancer: an overview..Cancers (Basel)2014;6:1769-92 PMCID:PMC4190567

[4] Kobayashi S,Dayaram T,Kocher O.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib..N Engl J Med2005;352:786-92

[5] Shah NP,Lee FY,Norris D.Overriding imatinib resistance with a novel ABL kinase inhibitor..Science2004;305:399-401

[6] 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

[7] Recupero D,Marchio C,Castellano I.Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines..J Pathol2013;229:390-9

[8] Duncan JS,Nakamura K,Midland AA.Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer..Cell2012;149:307-21 PMCID:PMC3328787

[9] Zawistowski JS,Goulet DR,Beltran AS.Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex..Cancer Discov2017;7:302-21 PMCID:PMC5340640

[10] Tao Z,Lu C,Zhang Z.Breast cancer: epidemiology and etiology..Cell Biochem Biophys2015;72:333-8

[11] Sorlie T,Tibshirani R,Geisler S.Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications..Proc Natl Acad Sci U S A2001;98:10869-74 PMCID:PMC58566

[12] Perou CM,Eisen MB,Jeffrey SS.Molecular portraits of human breast tumours..Nature2000;406:747-52

[13] Sanchez-Vega F,Armenia J,Luna A.Oncogenic signaling pathways in the cancer genome Atlas..Cell2018;173:321-37.e10 PMCID:PMC6070353

[14] Lemmon MA.Cell signaling by receptor tyrosine kinases..Cell2010;141:1117-34 PMCID:PMC2914105

[15] Tokunaga E,Egashira A,Morita M.Deregulation of the Akt pathway in human cancer..Curr Cancer Drug Targets2008;8:27-36

[16] Lopez-Knowles E,McNeil CM,Qiu MR.PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality..Int J Cancer2010;126:1121-31

[17] Stephens PJ,Davies H,Greenman C.The landscape of cancer genes and mutational processes in breast cancer..Nature2012;486:400-4 PMCID:PMC3428862

[18] Shapiro P.Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy..Crit Rev Clin Lab Sci2002;39:285-330

[19] Corkery B,Clynes M.Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer..Ann Oncol2009;20:862-7

[20] Hoadley KA,Fan C,He X.EGFR associated expression profiles vary with breast tumor subtype..BMC Genomics2007;8:258 PMCID:PMC2014778

[21] Dent R,Pritchard KI,Kahn HK.Triple-negative breast cancer: clinical features and patterns of recurrence..Clin Cancer Res2007;13:4429-34

[22] Crown J,Gullo G.Emerging targeted therapies in triple-negative breast cancer..Ann Oncol2012;23 Suppl 6:vi56-65

[23] Kalimutho M,Mittal D,Srihari S.Targeted therapies for triple-negative breast cancer: combating a stubborn disease..Trends Pharmacol Sci2015;36:822-46

[24] Rinehart J,Lorusso PM,Hecht JR.Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer..J Clin Oncol2004;22:4456-62

[25] Adjei AA,Franklin W,Wilson D.Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers..J Clin Oncol2008;26:2139-46 PMCID:PMC2718422

[26] Hoeflich KP,Boyd Z,Guerrero S.In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models..Clin Cancer Res2009;15:4649-64

[27] Mirzoeva OK,Heiser LM,Siwak D.Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition..Cancer Res2009;69:565-72 PMCID:PMC2737189

[28] Li X,Jiang J.ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling..Cell Signal2008;20:2145-55 PMCID:PMC2613789

[29] Yu CF,Cantley LG.ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase..J Biol Chem2002;277:19382-8

[30] Turke AB,Costa C,Arteaga CL.MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors..Cancer Res2012;72:3228-37 PMCID:PMC3515079

[31] Yoon YK,Han SW,Oh DY.Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells..Mol Cancer Ther2009;8:2526-36

[32] Ebi H,Singh A,Song Y.Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers..J Clin Invest2011;121:4311-21 PMCID:PMC3204842

[33] Wong GS,Liu JB,Xu X.Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition..Nat Med2018;24:968-77 PMCID:PMC6039276

[34] Mainardi S,Prahallad A,Bosma A.SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo..Nat Med2018;24:961-7

[35] Ruess DA,Ciecielski KJ,Berninger A.Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase..Nat Med2018;24:954-60

[36] Ahmed TA,Karoulia Z,Sachidanandam R.SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors..Cell Rep2019;26:65-78.e5 PMCID:PMC6396678

[37] Fedele C,Diskin B,Jen J.SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models..Cancer Discov2018;8:1237-49 PMCID:PMC6170706

[38] Matalkah F,Zhao H.SHP2 acts both upstream and downstream of multiple receptor tyrosine kinases to promote basal-like and triple-negative breast cancer..Breast Cancer Res2016;18:2 PMCID:PMC4700603

[39] Miller MA,Sullivan RJ,Meyer AS.Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance..Cancer Discov2016;6:382-99 PMCID:PMC5087317

[40] Tao JJ,Radosevic-Robin N,Auricchio N.Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer..Sci Signal2014;7:ra29 PMCID:PMC4283215

[41] Verma N,Kothari C,Kedan A.Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 Axis..Cancer Res2017;77:86-99

[42] Vanhaesebroeck B,Graupera M.The emerging mechanisms of isoform-specific PI3K signalling..Nat Rev Mol Cell Biol2010;11:329-41

[43] Roskoski R Jr.Properties of FDA-approved small molecule protein kinase inhibitors..Pharmacol Res2019;144:19-50

[44] Kwitkowski VE,Ibrahim A,Justice R.FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma..Oncologist2010;15:428-35 PMCID:PMC3227966

[45] Massacesi C,Fretault N.Challenges in the clinical development of PI3K inhibitors..Ann N Y Acad Sci2013;1280:19-23 PMCID:PMC3666091

[46] Wee S,Maira SM,Miller C.PTEN-deficient cancers depend on PIK3CB..Proc Natl Acad Sci U S A2008;105:13057-62 PMCID:PMC2529105

[47] Torbett NE,Knight ZA,Moasser M.A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition..Biochem J2008;415:97-110 PMCID:PMC3079392

[48] Chia S,Joy AA,Gorr M.Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer..Curr Oncol2015;22:33-48 PMCID:PMC4324342

[49] O’Reilly KE,She QB,Mills GB.mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt..Cancer Res2006;66:1500-8 PMCID:PMC3193604

[50] Chakrabarty A,Kuba MG,Arteaga CL.Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors..Proc Natl Acad Sci U S A2012;109:2718-23 PMCID:PMC3286932

[51] Brunet A,Zigmond MJ,Juo P.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor..Cell1999;96:857-68

[52] Chandarlapaty S,Scaltriti M,Grbovic-Huezo O.AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity..Cancer Cell2011;19:58-71 PMCID:PMC3025058

[53] Ruiz-Saenz A,Campbell MR,Gulizia N.HER2 amplification in tumors activates PI3K/Akt signaling independent of HER3..Cancer Res2018;78:3645-58 PMCID:PMC6779043

[54] Chakrabarty A,Wang SE,Engelman JA.H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3..Oncogene2010;29:5193-203 PMCID:PMC2945381

[55] Garrett JT,Kuba MG,Arteaga CL.Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function..Clin Cancer Res2013;19:610-9 PMCID:PMC3563762

[56] Zhang J,Schmit F,Eck MJ.CRKL mediates p110β-dependent PI3K signaling in PTEN-deficient cancer cells..Cell Rep2017;20:549-57 PMCID:PMC5704918

[57] Cancer Genome Atlas Research Network,Collisson EA,Shaw KR.The cancer genome Atlas Pan-cancer analysis project..Nat Genet2013;45:1113-20 PMCID:PMC3919969

[58] Rexer BN,Dahlman K.Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells..Breast Cancer Res2014;16:R9 PMCID:PMC3978602

[59] Schwarz LJ,Rexer BN,Gonzalez Ericsson PI.An ERBB1-3 neutralizing antibody mixture with high activity against drug-resistant HER2+ breast cancers with ERBB ligand overexpression.J Natl Cancer Inst2017;109: PMCID:PMC6543617

[60] Carracedo A,Teruya-Feldstein J,Salmena L.Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer..J Clin Invest2008;118:3065-74 PMCID:PMC2518073

[61] Serra V,Prudkin L,Ibrahim YH.PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer..Oncogene2011;30:2547-57 PMCID:PMC3107390

[62] Will M,Toy W,Rodrik-Outmezguine V.Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling..Cancer Discov2014;4:334-47 PMCID:PMC4049524

[63] Matkar S,Hua X.Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop..Am J Cancer Res2017;7:1476-85 PMCID:PMC5523029

[64] Cheng H,Ohlson C,Symonds L.PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling..Oncogene2016;35:2961-70 PMCID:PMC4896860

[65] Sato N,Nakatsuji M,Shimoji N.MEK and PI3K catalytic activity as predictor of the response to molecularly targeted agents in triple-negative breast cancer..Biochem Biophys Res Commun2017;489:484-9

[66] Schwartz S,Trigwell CB,Carver BS.Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta..Cancer Cell2015;27:109-22 PMCID:PMC4293347

[67] Costa C,Martini M,Faber AC.Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer..Cancer Cell2015;27:97-108 PMCID:PMC4745884

[68] Lynch JT,Hancox U,Maynard J.Combined inhibition of PI3Kbeta and mTOR inhibits growth of PTEN-null tumors..Mol Cancer Ther2018;17:2309-19

[69] Elkabets M,Juric D,Mino-Kenudson M.mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer..Sci Transl Med2013;5:196ra99 PMCID:PMC3935768

[70] Vora SR,Kim N,Huynh T.CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors..Cancer Cell2014;26:136-49 PMCID:PMC4155598

[71] Stratikopoulos EE,Szabolcs M,Lefebvre C.Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy..Cancer Cell2015;27:837-51 PMCID:PMC4918409

[72] Stuhlmiller TJ,Zawistowski JS,Beltran AS.Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains..Cell Rep2015;11:390-404 PMCID:PMC4408261

[73] Britschgi A,Brinkhaus H,Romanet V.JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer..Cancer Cell2012;22:796-811

[74] Yang L,Sun Y.An IL6-STAT3 loop mediates resistance to PI3K inhibitors by inducing epithelial-mesenchymal transition and cancer stem cell expansion in human breast cancer cells..Biochem Biophys Res Commun2014;453:582-7

[75] Yang W,Marotti JD,Traphagen NA.Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer..Oncotarget2018;9:8810-22 PMCID:PMC5823630

[76] Yardley DA,Pritchard KI,Baselga J.Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis..Adv Ther2013;30:870-84 PMCID:PMC3898123

[77] Clement E,Nihira NT,Toker A.Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors..Sci Signal2018;11: PMCID:PMC5902813

[78] Nguyen LK.Feedback regulation in cell signalling: lessons for cancer therapeutics..Semin Cell Dev Biol2016;50:85-94

[79] Fabian Z,Nguyen LK.Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling..J Mol Med (Berl)2016;94:377-90

[80] Nguyen LK.Dynamics of ubiquitin-mediated signalling: insights from mathematical modelling and experimental studies..Brief Bioinform2016;17:479-93

[81] Shin S.Dissecting cell-fate determination through integrated modelling of the ERK/MAPK signalling pathway.ERK Signaling: Methods Molecular Biology2016;

[82] Kolch W,Granovskaya M.The dynamic control of signal transduction networks in cancer cells..Nat Rev Cancer2015;15:515-27

[83] Claas AM,Gordonov S,Lauffenburger DA.Systems modeling identifies divergent receptor tyrosine kinase reprogramming to MAPK pathway inhibition..Cell Mol Bioeng2018;11:451-69 PMCID:PMC6244947

[84] Romano D,Matallanas D,Doherty C.Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling..Nat Cell Biol2014;16:673-84

[85] Byrne KM,Dawson JC,Bukowski-Wills JC.Bistability in the Rac1, PAK, and RhoA signaling network drives actin cytoskeleton dynamics and cell motility switches..Cell Syst2016;2:38-48 PMCID:PMC4802415

[86] Shin SY.Unveiling hidden dynamics of hippo signalling: a systems analysis..Genes2016;7:44 PMCID:PMC4999832

[87] Varusai TM.Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR..Sci Rep2018;8:643 PMCID:PMC5766521

[88] Fitzgerald JB,Nielsen UB.Systems biology and combination therapy in the quest for clinical efficacy..Nat Chem Biol2006;2:458-66

[89] Shin SY,Verma N,Nguyen LK.Systems modelling of the EGFR-PYK2-c-Met interaction network predicts and prioritizes synergistic drug combinations for triple-negative breast cancer..PLoS Comput Biol2018;14:e1006192 PMCID:PMC6007894

[90] Feala JD,Duxbury PM,McCulloch AD.Systems approaches and algorithms for discovery of combinatorial therapies..Wiley Interdiscip Rev Syst Biol Med2010;2:181-93

[91] Fey D,Dreidax D,Hastings JF.Signaling pathway models as biomarkers: patient-specific simulations of JNK activity predict the survival of neuroblastoma patients..Sci Signal2015;8:ra130

[92] Shin SY,Verma N,Nguyen LK.Systems modelling of the EGFR-PYK2-c-Met interaction network predicts and prioritizes synergistic drug combinations for triple-negative breast cancer..PLoS Comput Biol2018;14:e1006192 PMCID:PMC6007894

[93] Li XM,Dumitru M,Filipski E.A circadian clock transcription model for the personalization of cancer chronotherapy..Cancer Res2013;73:7176-88

[94] Faratian D,Lebedeva G,Moodie S.Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab..Cancer Res2009;69:6713-20

[95] Nguyen LK,Croucher DR,Kholodenko BN.Signalling by protein phosphatases and drug development: a systems-centred view..FEBS J2013;280:751-65 PMCID:PMC3368988

[96] Kolch W.Personalized computational models as biomarkers..J Pers Med2017;7:E9 PMCID:PMC5618155

[97] Nguyen LK.Feedback regulation in cell signalling: Lessons for cancer therapeutics..Semin Cell Dev Biol2016;50:85-94