Tumors with mutant BRAF or mutant KRAS are dependent on ERK signaling and sensitive to MEK inhibitors, but only the BRAF mutant tumors are sensitive to RAF inhibitors. We have shown that RAF inhibitors allosterically activate RAS-dependent F?AF dimers in most normal and tumor cells and thus paradoxically activate signaling. However, in tumors with V600E BRAF mutation, activated ERK causes feedback inhibition of RAS.GTP to a levels too low to support RAF dimerization and in this context V600E signals as a monomer. RAF inhibitors bind to the monomer and potently inhibit ERK signaling in these tumors. This is basis for the dramatic therapeutic response of melanomas with codon 600 BRAF mutation to these drugs compared to MEK inhibitors. However, tumor responses are incomplete and often temporary. Tumor progression is due to acquired resistance often characterized by insensitivity of ERK signaling to the RAF inhibitor. We have shown that this may be mediated by induction of RAS.GTP or to splice variants of RAF that dimerize in a Ras-independent manner. We also believe that the initial tumor response is limited by adaptation of the tumor to inhibition of ERK. In RAS and BRAF mutant tumors, ERK activation causes the feedback inhibition of other intracellular signaling pathways and renders the cell dependent on ERK signaling. This causes hypersensitivity to RAF inhibitors (mutant BRAF tumors) or MEK inhibitors (mutant BRAF and some KRAS tumors). However, inhibition of ERK signaling with these drugs relieves this feedback, attenuates inhibition of ERK output, and activates other mitogenic signaling pathway that cause adaptive resistance to ERK inhibition. Our goals in this proposal are to develop therapies that maximally inhibit ERK output by combining RAF or MEK inhibitors with selective MEK and RTK inhibitors that prevent feedback reactivation of RAF. We hypothesize that maximal inhibition of ERK output with these regimens will relieve feedback inhibition of receptor tyrosine kinase signaling and cause resistance in that manner. We will identify these reactivated pathways and then develop and test therapies based on maximal ERK inhibition combined with inhibition of key reactivated receptors to prevent or limit adaptive resistance.
Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This project addresses the two critical roadblocks to improving the care and curability of persons with lung adenocarcinomas: (1) understanding how adenocarcinomas spread to the brain (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung.
|Yu, Helena A; Arcila, Maria E; Harlan Fleischut, Megan et al. (2014) Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol 9:554-8|
|Meador, Catherine B; Micheel, Christine M; Levy, Mia A et al. (2014) Beyond histology: translating tumor genotypes into clinically effective targeted therapies. Clin Cancer Res 20:2264-75|
|Valiente, Manuel; Obenauf, Anna C; Jin, Xin et al. (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156:1002-16|
|de Bruin, Elza C; Cowell, Catherine; Warne, Patricia H et al. (2014) Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov 4:606-19|
|Rekhtman, Natasha; Borsu, Laetitia; Reva, Boris et al. (2014) Unsuspected collision of synchronous lung adenocarcinomas: a potential cause of aberrant driver mutation profiles. J Thorac Oncol 9:e1-3|
|Yu, H A; Arcila, M E; Hellmann, M D et al. (2014) Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol 25:423-8|
|Lovly, Christine M; McDonald, Nerina T; Chen, Heidi et al. (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027-34|
|Yu, Helena A; Riely, Gregory J; Lovly, Christine M (2014) Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 20:5898-907|
|Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling et al. (2014) Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep 7:999-1008|
|Haq, Rizwan; Fisher, David E; Widlund, Hans R (2014) Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation. Clin Cancer Res 20:2257-63|
Showing the most recent 10 out of 59 publications