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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
4P01CA129243-10
Application #
9142257
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Yu, Helena A; Planchard, David; Lovly, Christine M (2018) Sequencing Therapy for Genetically Defined Subgroups of Non-Small Cell Lung Cancer. Am Soc Clin Oncol Educ Book :726-739
Yuan, Tina L; Amzallag, Arnaud; Bagni, Rachel et al. (2018) Differential Effector Engagement by Oncogenic KRAS. Cell Rep 22:1889-1902
Ruscetti, Marcus; Leibold, Josef; Bott, Matthew J et al. (2018) NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362:1416-1422
Du, Zhenfang; Lovly, Christine M (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17:58
Yu, Helena A; Suzawa, Ken; Jordan, Emmet et al. (2018) Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance. Clin Cancer Res 24:3108-3118
Westover, D; Zugazagoitia, J; Cho, B C et al. (2018) Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol 29:i10-i19
Li, Bob T; Shen, Ronglai; Buonocore, Darren et al. (2018) Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial. J Clin Oncol 36:2532-2537
Fan, Pang-Dian; Narzisi, Giuseppe; Jayaprakash, Anitha D et al. (2018) YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics. Proc Natl Acad Sci U S A 115:E6030-E6038
Mo, Qianxing; Shen, Ronglai; Guo, Cui et al. (2018) A fully Bayesian latent variable model for integrative clustering analysis of multi-type omics data. Biostatistics 19:71-86
Childress, Merrida A; Himmelberg, Stephen M; Chen, Huiqin et al. (2018) ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties. Mol Cancer Res 16:1724-1736

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