WZ4002 inhibits EGFR phosphorylation and induces significant tumor regression in murine models of EGFR T790M
Our studies identify a novel structural class of EGFR kinase inhibitors which are effective in vitro and in vivo models harboring the EGFR T790M mutation. Given the dramatic activity in models with established EGFR T790M, we determined whether WZ4002 treatment could also prevent the development of EGFR T790M using in vitro models harboring EGFR activating mutations. Unlike with gefitinib or HKI-272, which when used at their achievable plasma concentrations lead to development of EGFR T790M in vitro13,21,22, we were unable to isolate any EGFR T790M containing clones from WZ4002 treated Ba/F3 or PC9 NSCLC cells (Table S9). These findings suggest that WZ4002 could also be used as initial therapy for EGFR mutant NSCLC patients and may ultimately lead to a longer time to disease progression than currently achieved with gefitinib1.
Mutations, including at the gatekeeper residue, are a common mechanism of drug resistance to kinase inhibitors. The current approach, using a cellular screen expressing the mutant kinase of interest, can be applied to identify novel agents specifically against drug resistance or oncogenic mutations implicated in human cancers. Such agents may truly be cancer selective and clinically more potent and less toxic than those that also concurrently inhibit the wild type kinase. The agents described here are unique in that they inhibit both the drug sensitizing and resistance mutations but are selective against WT EGFR23,24,25. Further studies are needed to determine whether this class of EGFR inhibitors will be clinically effective in patients with EGFR mutant cancers harboring EGFR T790M mediated acquired drug resistance.
Results: In vitro and in vivo pharmacology studies were conducted to evaluate CO-1686 potency in four EGFR
mutations common in NSCLC patients: L858R, delE746-A750, L858R/T790M and delE746-A750/T790M. CO-1686
was shown to be active against all four EGFR mutants. Effects of CO-1686 on cell proliferation and EGFR signaling
were evaluated in HCC827 cells (delE746-A750) and its erlotinib-resistant clone, HCC827-EPR harboring the second
site mutation T790M (delE746-A750/T790M). CO-1686 inhibited cell proliferation in both cell lines equally. In mouse
xenograft studies, oral dosing of CO-1686 in double mutant (L858R/T790M) and in single mutant (delE746-A750)
models caused tumor shrinkage as a single agent in a dose-dependent manner. Different dosing schedules were
explored.
Conclusions: Our results establish CO-1686 as a potent, mutant-selective EGFR inhibitor with excellent in vivo
activity in mice bearing tumors with activating EGFR mutations as well as the resistance mutation T790M. These data
suggest that treatment with CO-1686 as a single agent may overcome T790M-mediated drug resistance in NSCLC.
Initially, clinical development will focus on NSCLC patients with mutant EGFR.
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