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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Chen, Qing; Boire, Adrienne; Jin, Xin et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493-8
Hames, Megan L; Chen, Heidi; Iams, Wade et al. (2016) Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer☆. Lung Cancer 92:29-34
Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18
Lito, Piro; Solomon, Martha; Li, Lian-Sheng et al. (2016) Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351:604-8
Malladi, Srinivas; Macalinao, Danilo G; Jin, Xin et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165:45-60
Konduri, Kartik; Gallant, Jean-Nicolas; Chae, Young Kwang et al. (2016) EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discov 6:601-11
Dragani, Tommaso A; Castells, Antoni; Kulasingam, Vathany et al. (2016) Major milestones in translational oncology. BMC Med 14:110
Manchado, Eusebio; Weissmueller, Susann; Morris 4th, John P et al. (2016) A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534:647-51
Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582
Massagué, Joan; Obenauf, Anna C (2016) Metastatic colonization by circulating tumour cells. Nature 529:298-306

Showing the most recent 10 out of 157 publications