REFERENCES
2. Rueff J, Rodrigues AS. Cancer drug resistance: a brief overview from a genetic viewpoint. Methods Mol Biol 2016;1395:1-18.
3. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014;6:1769-92.
4. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-92.
5. Shah NP, Tran C, Lee FY, Chen P, Norris D, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399-401.
6. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876-80.
7. Recupero D, Daniele L, Marchio C, Molinaro L, Castellano I, et al. Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines. J Pathol 2013;229:390-9.
8. Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 2012;149:307-21.
9. Zawistowski JS, Bevill SM, Goulet DR, Stuhlmiller TJ, Beltran AS, et al. Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov 2017;7:302-21.
10. Tao Z, Shi A, Lu C, Song T, Zhang Z, et al. Breast cancer: epidemiology and etiology. Cell Biochem Biophys 2015;72:333-8.
11. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74.
12. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52.
13. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, et al. Oncogenic signaling pathways in the cancer genome Atlas. Cell 2018;173:321-37.e10.
15. Tokunaga E, Oki E, Egashira A, Sadanaga N, Morita M, et al. Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets 2008;8:27-36.
16. Lopez-Knowles E, O’Toole SA, McNeil CM, Millar EK, Qiu MR, et al. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 2010;126:1121-31.
17. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012;486:400-4.
18. Shapiro P. Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy. Crit Rev Clin Lab Sci 2002;39:285-330.
19. Corkery B, Crown J, Clynes M, O’Donovan N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol 2009;20:862-7.
20. Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 2007;8:258.
21. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429-34.
22. Crown J, O’Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol 2012;23 Suppl 6:vi56-65.
23. Kalimutho M, Parsons K, Mittal D, Lopez JA, Srihari S, et al. Targeted therapies for triple-negative breast cancer: combating a stubborn disease. Trends Pharmacol Sci 2015;36:822-46.
24. Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, et al. 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 Oncol 2004;22:4456-62.
25. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, et al. 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 Oncol 2008;26:2139-46.
26. Hoeflich KP, O’Brien C, Boyd Z, Cavet G, Guerrero S, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 2009;15:4649-64.
27. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009;69:565-72.
28. Li X, Huang Y, Jiang J, Frank SJ. ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. Cell Signal 2008;20:2145-55.
29. Yu CF, Liu ZX, Cantley LG. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem 2002;277:19382-8.
30. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 2012;72:3228-37.
31. Yoon YK, Kim HP, Han SW, Hur HS, Oh DY, et al. Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. Mol Cancer Ther 2009;8:2526-36.
32. Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, et al. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 2011;121:4311-21.
33. Wong GS, Zhou J, Liu JB, Wu Z, Xu X, et al. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 2018;24:968-77.
34. Mainardi S, Mulero-Sanchez A, Prahallad A, Germano G, Bosma A, et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med 2018;24:961-7.
35. Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med 2018;24:954-60.
36. Ahmed TA, Adamopoulos C, Karoulia Z, Wu X, Sachidanandam R, et al. SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors. Cell Rep 2019;26:65-78.e5.
37. Fedele C, Ran H, Diskin B, Wei W, Jen J, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov 2018;8:1237-49.
38. Matalkah F, Martin E, Zhao H, Agazie YM. SHP2 acts both upstream and downstream of multiple receptor tyrosine kinases to promote basal-like and triple-negative breast cancer. Breast Cancer Res 2016;18:2.
39. Miller MA, Oudin MJ, Sullivan RJ, Wang SJ, Meyer AS, et al. Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance. Cancer Discov 2016;6:382-99.
40. Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal 2014;7:ra29.
41. Verma N, Muller AK, Kothari C, Panayotopoulou E, Kedan A, et al. Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 Axis. Cancer Res 2017;77:86-99.
42. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 2010;11:329-41.
43. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res 2019;144:19-50.
44. Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 2010;15:428-35.
45. Massacesi C, di Tomaso E, Fretault N, Hirawat S. Challenges in the clinical development of PI3K inhibitors. Ann N Y Acad Sci 2013;1280:19-23.
46. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A 2008;105:13057-62.
47. Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, et al. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 2008;415:97-110.
48. Chia S, Gandhi S, Joy AA, Edwards S, Gorr M, et al. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. Curr Oncol 2015;22:33-48.
49. O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8.
50. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A 2012;109:2718-23.
51. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-68.
52. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19:58-71.
53. Ruiz-Saenz A, Dreyer C, Campbell MR, Steri V, Gulizia N, et al. HER2 amplification in tumors activates PI3K/Akt signaling independent of HER3. Cancer Res 2018;78:3645-58.
54. Chakrabarty A, Rexer BN, Wang SE, Cook RS, Engelman JA, et al. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 2010;29:5193-203.
55. Garrett JT, Sutton CR, Kuba MG, Cook RS, Arteaga CL. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin Cancer Res 2013;19:610-9.
56. Zhang J, Gao X, Schmit F, Adelmant G, Eck MJ, et al. CRKL mediates p110β-dependent PI3K signaling in PTEN-deficient cancer cells. Cell Rep 2017;20:549-57.
57. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, Mills GB, Shaw KR, et al. The cancer genome Atlas Pan-cancer analysis project. Nat Genet 2013;45:1113-20.
58. Rexer BN, Chanthaphaychith S, Dahlman K, Arteaga CL. Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells. Breast Cancer Res 2014;16:R9.
59. Schwarz LJ, Hutchinson KE, Rexer BN, Estrada MV, Gonzalez Ericsson PI, et al. An ERBB1-3 neutralizing antibody mixture with high activity against drug-resistant HER2+ breast cancers with ERBB ligand overexpression. J Natl Cancer Inst 2017;109.
60. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-74.
61. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57.
62. Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov 2014;4:334-47.
63. Matkar S, An C, Hua X. Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop. Am J Cancer Res 2017;7:1476-85.
64. Cheng H, Liu P, Ohlson C, Xu E, Symonds L, et al. PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 2016;35:2961-70.
65. Sato N, Wakabayashi M, Nakatsuji M, Kashiwagura H, Shimoji N, et al. MEK and PI3K catalytic activity as predictor of the response to molecularly targeted agents in triple-negative breast cancer. Biochem Biophys Res Commun 2017;489:484-9.
66. Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, et al. Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell 2015;27:109-22.
67. Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, et al. Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer. Cancer Cell 2015;27:97-108.
68. Lynch JT, Polanska UM, Hancox U, Delpuech O, Maynard J, et al. Combined inhibition of PI3Kbeta and mTOR inhibits growth of PTEN-null tumors. Mol Cancer Ther 2018;17:2309-19.
69. Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med 2013;5:196ra99.
70. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-49.
71. Stratikopoulos EE, Dendy M, Szabolcs M, Khaykin AJ, Lefebvre C, et al. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell 2015;27:837-51.
72. Stuhlmiller TJ, Miller SM, Zawistowski JS, Nakamura K, Beltran AS, et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains. Cell Rep 2015;11:390-404.
73. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 2012;22:796-811.
74. Yang L, Han S, 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 Commun 2014;453:582-7.
75. Yang W, Schwartz GN, Marotti JD, Chen V, Traphagen NA, et al. Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer. Oncotarget 2018;9:8810-22.
76. Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 2013;30:870-84.
77. Clement E, Inuzuka H, Nihira NT, Wei W, Toker A. Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. Sci Signal 2018;11.
78. Nguyen LK, Kholodenko BN. Feedback regulation in cell signalling: lessons for cancer therapeutics. Semin Cell Dev Biol 2016;50:85-94.
79. Fabian Z, Taylor CT, 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 Bioinform 2016;17:479-93.
81. Shin S, Nguyen LK. Dissecting cell-fate determination through integrated modelling of the ERK/MAPK signalling pathway. ERK Signaling: Methods Molecular Biology 2016; doi: 10.1007/978-1-4939-6424-6_29.
82. Kolch W, Halasz M, Granovskaya M, Kholodenko BN. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer 2015;15:515-27.
83. Claas AM, Atta L, Gordonov S, Meyer AS, Lauffenburger DA. Systems modeling identifies divergent receptor tyrosine kinase reprogramming to MAPK pathway inhibition. Cell Mol Bioeng 2018;11:451-69.
84. Romano D, Nguyen LK, Matallanas D, Halasz M, Doherty C, et al. Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nat Cell Biol 2014;16:673-84.
85. Byrne KM, Monsefi N, Dawson JC, Degasperi A, Bukowski-Wills JC, et al. Bistability in the Rac1, PAK, and RhoA signaling network drives actin cytoskeleton dynamics and cell motility switches. Cell Syst 2016;2:38-48.
86. Shin SY, Nguyen LK. Unveiling hidden dynamics of hippo signalling: a systems analysis. Genes 2016;7:44.
87. Varusai TM, Nguyen LK. Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR. Sci Rep 2018;8:643.
88. Fitzgerald JB, Schoeberl B, Nielsen UB, Sorger PK. Systems biology and combination therapy in the quest for clinical efficacy. Nat Chem Biol 2006;2:458-66.
89. Shin SY, Muller AK, Verma N, Lev S, 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 Biol 2018;14:e1006192.
90. Feala JD, Cortes J, Duxbury PM, Piermarocchi C, McCulloch AD, et al. Systems approaches and algorithms for discovery of combinatorial therapies. Wiley Interdiscip Rev Syst Biol Med 2010;2:181-93.
91. Fey D, Halasz M, Dreidax D, Kennedy SP, Hastings JF, et al. Signaling pathway models as biomarkers: patient-specific simulations of JNK activity predict the survival of neuroblastoma patients. Sci Signal 2015;8:ra130.
92. Shin SY, Müller AK, Verma N, Lev S, 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 Biol 2018;14:e1006192.
93. Li XM, Mohammad-Djafari A, Dumitru M, Dulong S, Filipski E, et al. A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Res 2013;73:7176-88.
94. Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, et al. Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res 2009;69:6713-20.
95. Nguyen LK, Matallanas D, Croucher DR, von Kriegsheim A, Kholodenko BN. Signalling by protein phosphatases and drug development: a systems-centred view. FEBS J 2013;280:751-65.