Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency.
Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non-small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones.
McDermott
Ultan
U
Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Pusapati
Raju V
RV
Christensen
James G
JG
Gray
Nathanael S
NS
Settleman
Jeff
J
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077547:Crizotinib; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005784:Gene Amplification / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D011720:Pyrazoles; D011725:Pyridines / Q000627:therapeutic use; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
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; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007211:Indoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D017978:Receptors, Growth Factor; D013450:Sulfones; D000077547:Crizotinib; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met