Abstract 4734: Modeling acquired resistance to MAPK pathway inhibitors in KRAS mutant tumors

Abstract

Abstract Background: Acquired resistance to antitumor therapies underlies one of the challenges in effectively treating cancer. Understanding the mechanisms of acquired drug resistance may lead to elucidation of redundant oncogenic pathways and the development of more effective therapies. The RAS/RAF/MEK pathway is active in over 30% of human tumors, often due to mutation in BRAF or RAS family members. Several MEK inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in various stages of clinical development. These inhibitors are allosteric and act by binding to a hydrophobic pocket adjacent to the ATP binding pocket to inhibit MEK kinase activity. Preclinical studies using randomly mutagenized MEK cDNAs have identified mutations in MEK that upon transfection in MEK sensitive lines can render them resistant to MEK inhibitors. The strongest effects were observed with mutations affecting the allosteric binding pocket, thus blocking inhibitor binding. Results: To model acquired resistance to MEK inhibitors 3 independent KRAS mutant tumor cell lines (breast MDA-MB-231, colon HCT116 and LoVo) were grown in the presence of increasing concentrations of the selective MEK inhibitor PD0325901 and pools of MEK resistant cells were characterized versus parental cells. MEK resistant cells were still dependent on the MAPK pathway and sensitive to treatment with inhibitors against the downstream kinase ERK. In all three lines, MEK resistance was associated with acquisition of mutations in the MEK allosteric binding pocket, resulting in lack of signaling inhibition and suggesting that such resistance can arise relatively rapidly and in distinct tumor types. To compare mechanisms of acquired resistance to ERK inhibitors, we also generated HCT116 cells resistant to a selective ERK inhibitor. ERK resistant lines remained sensitive to MEK inhibitors and dependent on the MAPK pathway. Conclusions: Acquired resistance to MEK inhibitors in KRAS mutant cells arises through mutations in MEK that block inhibitor binding so that the inhibitor is no longer effective. In this case, tumors remain dependent on the MAPK pathway and can be targeted by inhibitors that act downstream of mutated target. These studies provide the rationale for future screening of patients with acquired MEK inhibitor resistance for mutations in MEK1 and MEK2. Patients whose resistance is driven through MEK mutations may benefit from treatment with an ERK inhibitor. Combination of MEK and ERK inhibitors may potentially prevent or delay the onset of resistance in MAPK-addicted tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2011-4734