title: Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET.
abstract: Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non-small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR kinase domain mutations. Unfortunately, acquired resistance eventually emerges in these chronically treated cancers. Two of the most common mechanisms of acquired resistance to TKIs seen clinically are the acquisition of a secondary "gatekeeper" T790M EGFR mutation that increases the affinity of mutant EGFR for ATP and activation of MET to offset the loss of EGFR signaling. Although up to one-third of patient tumors resistant to reversible EGFR TKIs harbor concurrent T790M mutation and MET amplification, potential therapies for these tumors have not been modeled in vivo. In this study, we developed a preclinical platform to evaluate potential therapies by generating transgenic mouse lung cancer models expressing EGFR-mutant Del19-T790M or L858R-T790M, each with concurrent MET overexpression. We found that monotherapy targeting EGFR or MET alone did not produce significant tumor regression. In contrast, combination therapies targeting EGFR and MET simultaneously were highly efficacious against EGFR TKI-resistant tumors codriven by Del19-T790M or L858R-T790M and MET. Our findings therefore provide an in vivo model of intrinsic resistance to reversible TKIs and offer preclinical proof-of-principle that combination targeting of EGFR and MET may benefit patients with NSCLC.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.forename: Eiki
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cheng
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D066246:ErbB Receptors; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met