Mutations in four genes that encode components of mitogenic signaling pathways have been identified inhuman lung adenocarcinomas,including the EGFR, KRAS, HER2, and BRAF. Genetic models demonstratethat the activating mutations of KRAS, EGFR, and BRAF play a role in the pathogenesis of these tumors.These data suggest that agents that inhibit the function of these oncoprpteins could be important therapeuticagents in this disease. This is borne out by the clinical antitumor activity of EGFR inhibitors in tumors withEGFR mutation. Mutant KRAS is the most common of these lesions (detected in 25% ofadenocarcinomas),but unfortunately there is currently no drug that effectively inhibits this oncoprotein. The goal of this proposalis the development of therapeutic strategies that inhibit KRAS function. We hypothesize that advanced lungadenocarcinomas with mutant KRAS are still dependent on its function and that its effects are mediated byone or more of the KRAS effector proteins. These include RAF, PI3KCA, RAL-GDSand others. Ourpreliminary data show that a subset of lung adenocarcinomacell lines is sensitive to inhibition of MEKkinase, the downstreamtarget of RAF. Furthermore, tumors in which both KRAS and PI3KCA (encoding theP110alpha catalytic subunit of PI3K) are mutated are resistant to inhibition of either MEK or PI3K butsensitive to combined inhibition of both targets. We hypothesize lung adenocarcinomasthat are KRAS-mutant and PI3KCA wild type will be sensitive to MEK inhibition alone, and that additional tumors will besensitive to combined inhibition of both the MEK/MAPK and PI3K/AKT pathways. We propose now todetermine the dependence of mutant KRAS lung cancer cell lines on expression of KRAS and its effector-molecules, investigate the mechanisms underlying the MEK and PI3K dependence of these tumors, anddetermine the biologic and potential therapeutic consequences of MEK and PI3K/AKT inhibitors, alone andin combination, in lung adenocarcinomas.The eventual goal is the development of a strategy for thetreatment of KRAS-dependent lungadenocarcinoma.
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