Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors.
Therapies targeting receptor tyrosine kinases have shown efficacy in molecularly defined subsets of cancers. Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential. In this study, we examined how cancers become resistant to MET inhibitors, a class of drugs currently under clinical development. We utilized the highly sensitive gastric carcinoma cell line, SNU638, and two related MET inhibitors PHA-665752 and PF-2341066. To our surprise, we observed at least two mechanisms of resistance that arose simultaneously. Both resulted in maintenance of downstream PI3K (phosphoinositide 3-kinase)-AKT and MEK (MAP/ERK kinase)-ERK signaling in the presence of inhibitor. One mechanism, observed by modeling resistance both in vitro and in vivo, involved the acquisition of a mutation in the MET activation loop (Y1230). Structural analysis indicates that this mutation destabilizes the autoinhibitory conformation of MET and abrogates an important aromatic stacking interaction with the inhibitor. The other cause of resistance was activation of the epidermal growth factor receptor (EGFR) pathway due to increased expression of transforming growth factor α. Activation of EGFR bypassed the need for MET signaling to activate downstream signaling in these cells. This resistance could be overcome by combined EGFR and MET inhibition. Thus, therapeutic strategies that combine MET inhibitors capable of inhibiting Y1230 mutant MET in combination with anti-EGFR-based therapies may enhance clinical benefit for patients with MET-addicted cancers. Importantly, these results also underscore the notion that a single cancer can simultaneously develop resistance induced by several mechanisms and highlight the daunting challenges associated with preventing or overcoming resistance.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02129, USA.
Jie
J
Qi
Michele A
MA
McTigue
Andrew
A
Rogers
Eugene
E
Lifshits
James G
JG
Christensen
Pasi A
PA
Jänne
Jeffrey A
JA
Engelman
D000818:Animals; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D053492:Elafin / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C500984:CRTC1 protein, human; D053492:Elafin; D007211:Indoles; C506806:PI3 protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D017978:Receptors, Growth Factor; D013450:Sulfones; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D000077547:Crizotinib; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases
Cancer Metastasis Rev. 2008 Mar;27(1):85-94
18175071
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2316-21
16461907
Cancer Cell. 2008 Dec 9;14(6):485-93
19061839
Oncogene. 2004 Jul 8;23(31):5387-93
15064724
Curr Opin Genet Dev. 2008 Feb;18(1):73-9
18325754
Anticancer Agents Med Chem. 2009 Feb;9(2):221-9
19199866
J Clin Invest. 2008 Jul;118(7):2609-19
18568074
N Engl J Med. 2005 Feb 24;352(8):786-92
15728811
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4731-5
8197126
Cancer Res. 2007 Mar 1;67(5):2081-8
17332337
Cancer Cell. 2010 Jan 19;17(1):77-88
20129249
Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
14685170
Nat Genet. 1997 May;16(1):68-73
9140397
Mol Cancer Ther. 2008 Nov;7(11):3499-508
18974395
Biochemistry. 2009 Jun 16;48(23):5339-49
19459657
Science. 2001 Aug 3;293(5531):876-80
11423618
Blood. 2002 May 1;99(9):3472-5
11964322
Cancer Cell. 2002 Aug;2(2):117-25
12204532
Drug Metab Dispos. 2008 Jul;36(7):1267-74
18381487
Cancer Res. 2010 Feb 15;70(4):1524-33
20145145
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7
18093943
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11445-50
9326629
Clin Cancer Res. 2008 May 15;14(10):2895-9
18483355
J Biol Chem. 2008 Feb 1;283(5):2675-83
18055465
Science. 2007 May 18;316(5827):1039-43
17463250
N Engl J Med. 2008 Jul 24;359(4):366-77
18596266
PLoS Med. 2005 Mar;2(3):e73
15737014
N Engl J Med. 2006 Jun 15;354(24):2531-41
16775234
Cancer Res. 2008 Nov 15;68(22):9479-87
19010923
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3788-93
15731348
J Cell Physiol. 2007 Nov;213(2):316-25
17607709
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):701-6
9012848