MET activation confers resistance to cetuximab (Cmab) or panitumumab (Pmab) in colon cancer cell lines in vitro and in vivo. MET activation confers resistance.

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MET activation confers resistance to cetuximab (Cmab) or panitumumab (Pmab) in colon cancer cell lines in vitro and in vivo. MET activation confers resistance to cetuximab (Cmab) or panitumumab (Pmab) in colon cancer cell lines in vitro and in vivo. A, DiFiand LIM1215 cell lines were transduced with the following lentiviral vectors: MOCK (empty vector), MET, MET KD (kinase dead), or KRAS, then seeded in 96-well plates and cultured 7 days in the presence of vehicle (NT), cetuximab (1 μg/mL) or panitumumab (1 μg/mL), with or without the MET inhibitor JNJ-38877605 (250 nmol/L). B, DiFi and LIM1215 cells were treated for 1 week with increasing concentrations of cetuximab or panitumumab, with or without 20 ng/mL of HGF or HGF plus the MET inhibitor JNJ-38877605 (250 nmol/L). C, DiFi and LIM1215 cells were pretreated 24 hours with cetuximab (1 μg/mL), panitumumab (1 μg/mL), or JNJ-38877605 (250 nmol/L), then stimulated for 15 minutes with HGF (80 ng/mL) in the presence of the indicated inhibitors. Whole-cell extracts were then subjected to Western blot analysis and probed with the indicated antibodies. D, wild-type (wt) DiFi cells or DiFi transduced with HGF were subcutaneously injected in NOD/SCID mice. Upon tumor growth, mice were randomized (7 mice/group) and received intratumoral injection of saline/cetuximab or intratumoral injection of cetuximab and oral administration of JNJ-38877605. Arrows indicate treatment start. Alberto Bardelli et al. Cancer Discovery 2013;3:658-673 ©2013 by American Association for Cancer Research