Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic lung cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major impediment to cures or durable responses for patients treated with these therapies. A paradigm for the success of targeted therapies in lung cancer, comes from Epidermal Growth Factor Receptor (EGFR) mutant lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR are found in approximately 10- 15% of lung adenocarcinomas in the US. These mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) and four TKIs (erlotinib, gefitinib, afatinib and, most recently, osimertinib) are currently approved for the first-line treatment of EGFR mutant lung cancer. Acquired drug resistance, however, is a major challenge with all of these TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined. Data from our labs and others indicate that osimertinib resistance can arise through both EGFR-dependent mechanisms involving several different types of EGFR mutation and EGFR-independent mechanisms ? frequently epigenetic in origin ? that are poorly understood. Very little is known about the molecular context(s) in which these resistance mechanisms emerge, their frequency, biochemistry and how to target them pharmacologically. Given the speed of adoption of osimertinib as 1st line therapy, there is an urgent need to identify these mechanisms and resulting vulnerabilities. We propose to leverage our collective expertise in lung cancer biology, mouse models, resistance to targeted therapies and EGFR structural biology to address these issues. Using unique in vitro and in vivo models and patient resources of acquired resistance to osimertinib, innovative genomic and biochemical tools we will: 1) Identify molecular features and new therapeutic vulnerabilities of osimertinib-resistance EGFR variants. 2) Establish mutant EGFR heterodimerization patterns and determine whether these can be leveraged therapeutically to overcome osimertinib resistance; 3) Identify epigenetic processes that confer TKI resistance. Our studies will yield a comprehensive understanding of osimertinib resistance and insight with which to develop new mechanism-based approaches to target osimertinib-resistant tumors ? an urgent unmet clinical need.

Public Health Relevance

Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic EGFR mutant lung cancer. Despite this success, even the newest targeted therapies, like osimertinib, are not curative and acquired resistance is a major impediment to cures for patients. We will use our collective expertise in lung cancer biology, mouse models and EGFR structural biology to obtain a comprehensive understanding of osimertinib resistance and insight with which to develop new mechanism-based approaches to target osimertinib-resistant tumors ? an urgent unmet clinical need.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA196530-06
Application #
9854324
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Xiao, Qian; Wu, Jibo; Wang, Wei-Jia et al. (2018) DKK2 imparts tumor immunity evasion through ?-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med 24:262-270
Goldberg, Sarah B; Narayan, Azeet; Kole, Adam J et al. (2018) Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA. Clin Cancer Res 24:1872-1880
Gilles, Maud-Emmanuelle; Slack, Frank J (2018) Let-7 microRNA as a potential therapeutic target with implications for immunotherapy. Expert Opin Ther Targets 22:929-939
Nagarajan, Maxwell B; Tentori, Augusto M; Zhang, Wen Cai et al. (2018) Nonfouling, Encoded Hydrogel Microparticles for Multiplex MicroRNA Profiling Directly from Formalin-Fixed, Paraffin-Embedded Tissue. Anal Chem 90:10279-10285
Hartman, Douglas J; Ahmad, Fahad; Ferris, Robert L et al. (2018) Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma. Oral Oncol 86:278-287
Nagarajan, Arvindhan; Malvi, Parmanand; Wajapeyee, Narendra (2018) Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression. Front Endocrinol (Lausanne) 9:483
Rojewski, Alana M; Tanner, Nichole T; Dai, Lin et al. (2018) Tobacco Dependence Predicts Higher Lung Cancer and Mortality Rates and Lower Rates of Smoking Cessation in the National Lung Screening Trial. Chest 154:110-118
Chen, Ling; Azuma, Takeshi; Yu, Weiwei et al. (2018) B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U S A 115:3126-3131
Zhang, Jinhua; Song, Kun; Wang, Jun et al. (2018) S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor immunity. Oncoimmunology 7:e1296996
Anastasiadou, Eleni; Faggioni, Alberto; Trivedi, Pankaj et al. (2018) The Nefarious Nexus of Noncoding RNAs in Cancer. Int J Mol Sci 19:

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