Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset of NSCLC. Despite recent clinical progress with the use of specific targeted therapies, drug resistance remains a problem that limits patient survival. A promising strategy to combat cancer drug resistance is to deploy rational upfront polytherapies that suppress the survival and emergence of resistant tumor cells. However, in most tumors with oncogenic receptor kinases, the optimal initial polytherapy strategy is unclear because receptor kinases typically engage multiple effector pathways, and which of these individual pathways, if any, is most critical to tumor cell survival is poorly defined. We recently demonstrated in models of NSCLC harboring the recurrent oncogenic ALK receptor kinase fusion (EML4-ALK or ALK+) that the RAS-MAPK pathway, but not other known ALK effectors, is required for tumor cell survival. We revealed that EML4-ALK drives RAS-MAPK signaling by engaging all three major RAS isoforms (H, N-, K-RAS) via the HELP domain of EML4. MAPK pathway reactivation via either genomic amplification of KRASWT (wild-type) or downregulation of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibition. Accordingly, upfront ALK and MEK co-inhibition enhanced both the magnitude and duration of initial response in EML4-ALK NSCLC in vitro and in vivo models. Furthermore, genomic amplification (or gene duplication) of KRASWT or downregulation of DUSP6 was observed in ALK+ lung adenocarcinoma patients with acquired ALK inhibitor resistance. Together, our findings provided new insight into the function of RAS-MAPK signaling in EML4-ALK NSCLC and the rationale for upfront ALK + MEK inhibitor co-treatment to improve patient outcomes, a novel clinical trial we are leading. Moreover, the findings indicated an unanticipated role of the EML4 partner in EML4-ALK oncogene function and RAS signaling. Here, we will further extend our initial discovery to test the overall hypothesis that RAS activation and signaling is a hallmark of oncogenic ALK function in NSCLC.
In Aim 1, we will define the biological basis of RAS-MAPK signaling and dependence in EML4-ALK NSCLC, dissecting the molecular and cell biological control mechanisms governing RAS activation and signaling in ALK+ tumors.
In Aim 2, we will define the mechanism(s) that may limit curative response to ALK + MEK inhibitor polytherapy in ALK+ NSCLC patients, levering cutting-edge CRISPR-based genetic screening studies and patient tumor samples from our ALK + MEK inhibitor clinical trial. Overall, these multi-disciplinary, collaborative, patient-focused studies spanning biochemical, genetic, pharmacologic, cell biological, and patient cohort and tumor molecular analysis will provide fundamental insight into the function and control of RAS and oncogenic ALK signaling in cancer and further enhance our novel rational polytherapy strategy. Our ultimate goal is to ensure we transform ALK+ NSCLC from a lethal disease into a chronic or curable condition through biologically-based precision medicine.

Public Health Relevance

Advanced-stage cancer is a major public health problem because it is fast becoming the leading cause of death in the US. Treatments that specifically target proteins that drive cancer growth, such as RAF, MEK, ALK, and EGFR inhibitors, are leading to improved responses in many advanced-stage cancer patients, but success is limited because treatment resistance occurs. The studies in this grant proposal focus on the discovery of a new dominant mechanism of resistance to ALK targeted therapy in lung cancer. Findings from our studies will hopefully lead to improved treatments that eliminate resistance by allowing the design of optimal rational combination therapies. Our findings will have a major impact in the fight against cancer by optimizing targeted treatment strategies that will increase the survival of patients through precision medicine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211052-04
Application #
9840454
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Watson, Joanna M
Project Start
2017-01-11
Project End
2021-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Neel, Dana S; Allegakoen, David V; Olivas, Victor et al. (2018) Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res :
McCoach, Caroline E; Bivona, Trever G (2018) The evolving understanding of immunoediting and the clinical impact of immune escape. J Thorac Dis 10:1248-1252
Bugaj, L J; Sabnis, A J; Mitchell, A et al. (2018) Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science 361:
Zaman, Aubhishek; Bivona, Trever G (2018) Emerging application of genomics-guided therapeutics in personalized lung cancer treatment. Ann Transl Med 6:160
Nichols, Robert J; Haderk, Franziska; Stahlhut, Carlos et al. (2018) RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol 20:1064-1073
Neel, Dana S; Bivona, Trever G (2017) Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. NPJ Precis Oncol 1:
Blakely, Collin M; Watkins, Thomas B K; Wu, Wei et al. (2017) Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 49:1693-1704
Bivona, Trever G (2017) Dividing and conquering the variation among variants in EML4-ALK lung cancer. Transl Cancer Res 6:S369-S370
Ma, Pengfei; Fu, Yujie; Cai, Mei-Chun et al. (2017) Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer. Nat Commun 8:823
Hrustanovic, Gorjan; Olivas, Victor; Pazarentzos, Evangelos et al. (2015) RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med 21:1038-47