Lung P01 Competing (1/25/17) Project 2 (Rosen, PI) ABSTRACT This project is focused on the development of effective therapies for lung tumors driven by activation of the ERK signaling pathway, particularly those in which the pathway is driven by mutations in the KRAS or BRAF proto-oncogenes. These tumors are particularly difficult to treat, in part because there are no direct inhibitors of mutant KRAS or of dimer-dependent non-V600 BRAF mutations or fusions; in part because of adaptive resistance to RAF or MEK inhibitors, which is mediated by relief of ERK dependent feedback; in part because BRAF V600 tumors develop acquired resistance; and because of the toxicity of MEK inhibitors. In the last funding period we made material progress in overcoming these obstacles. We discovered that BRAF mutants fall into three functional classes based on their mechanism of activation; developed specific mechanism-based methods of inhibition of each class of mutant; identified novel equipotent inhibitors of RAF monomers and dimers for the treatment of Class 1 and 2 RAF mutants; identified MEK inhibitors with an enhanced ability to inhibit MEK driven by mutant RAS; and characterized and determined the mechanism of action of direct inhibitors of KRAS G12C, the most common mutant RAS allele in lung cancer. The goal of the proposal is to use these inhibitors to understand the role of each of these oncoproteins in lung cancer and pursue their preclinical development.
Aim 1 concerns the use of the RAF dimer/monomer inhibitor to understand the role of Class 2 dimer-dependent BRAF mutants and to develop treatment regimens for Class 1 and 2 mutants.
Aim 2 concerns the study of Class 3 BRAF mutants, the most common class in lung cancer, and exploits a novel mechanism for inhibiting their activity.
Aim 3 concerns the preclinical development of the KRAS G12C inhibitor and its use to study the functional role of mutant RAS in lung cancer and the consequences of its inhibition. Inhibiting ERK signaling driven by any of the mutants is expected to relieve ERK-dependent feedback inhibition of signaling and contribute to adaptive resistance. In collaboration with RP4, we will undertake the study of this process for each of these methods of inhibiting RAS/RAF/MEK signaling, attempt to identify pathways required for tumor cell survival, and develop combination therapy on this basis.

Public Health Relevance

Lung P01 Competing (1/25/17) Project 2 (Rosen, PI) PROJECT NARRATIVE The project proposes to develop effective regimens for the treatment of tumors dependent on dysregulation of the ERK pathway by mutant KRAS or BRAF. We have discovered three classes of BRAF mutants and developed specific regimens for the pharmacologic inhibition of each, as well as an allele-specific inhibitor of mutant KRAS G12C. We will use these regimens to understand the role of each of these mutants in lung cancer and pursue their development as therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA129243-11
Application #
9417593
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-09-13
Budget End
2019-08-31
Support Year
11
Fiscal Year
2018
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; Perez, Leslie; Chang, Qing et al. (2017) A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib. J Thorac Oncol 12:102-109
Ichihara, Eiki; Westover, David; Meador, Catherine B et al. (2017) SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer. Cancer Res 77:2990-3000
Yaeger, Rona; Yao, Zhan; Hyman, David M et al. (2017) Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. Cancer Res 77:6513-6523
Weigelt, Britta; Comino-Méndez, Iñaki; de Bruijn, Ino et al. (2017) Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer. Clin Cancer Res 23:6708-6720
Pal, Debjani; Pertot, Anja; Shirole, Nitin H et al. (2017) TGF-? reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells. Elife 6:
Yu, H A; Sima, C; Feldman, D et al. (2017) Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol 28:278-284
Boire, Adrienne; Zou, Yilong; Shieh, Jason et al. (2017) Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell 168:1101-1113.e13
Nieto, Patricia; Ambrogio, Chiara; Esteban-Burgos, Laura et al. (2017) A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548:239-243
Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S et al. (2017) Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548:234-238
Drilon, Alexander; Somwar, Romel; Wagner, Jacob P et al. (2016) A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer. Clin Cancer Res 22:2351-8

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