Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States. Over the last decade, a number of new therapies targeting signaling pathways that control cell growth and survival have been developed. Some of these, particularly tyrosine kinase inhibitors (TKIs), have shown remarkable antitumor activity in select subsets of lung cancer patients. Examples include gefitinib or erlotinib for EGFR- mutant lung cancers and more recently, crizotinib (PF-02341066) for lung cancers harboring chromosomal rearrangements of ALK (anaplastic lymphoma kinase). These therapies often induce marked responses and clinical remissions;however, cancers invariably develop resistance to TKI therapy, usually within one year of treatment. This type of resistance is termed acquired resistance, and it has severely curbed the impact of these new therapies. In this application, we will focus on ALK-positive lung cancers which affect approximately 8,000 people per year in the United States alone. We have previously shown that the lung cancer patients most likely to harbor ALK rearrangements are the young, never smokers with the adenocarcinoma type of NSCLC. In a seminal phase 1 trial led by our institution, crizotinib induced significant responses in close to 60% of ALK-positive patients, and stabilized disease in an additional 30%. Most patients, however, relapse after approximately one year due to acquired resistance, and there are currently no second-line options for these resistant patients other than standard chemotherapy. Here, we propose methods to discover molecular mechanisms underlying acquired resistance to crizotinib. We will generate laboratory models of ALK-positive NSCLC from patients with the disease. Models that are not already resistant will be made resistant in the laboratory using methodology that we previously used to identify clinically validated mechanisms of EGFR TKI resistance. We will systematically assess each model for the presence of resistance mutations within ALK itself, for activation of alternative growth pathways that allow cells to bypass ALK, and for defects in the cell death machinery. We will also take more unbiased approaches like gene expression profiling and comparative genomic hybridization to discover potentially novel mechanisms of resistance. Based on our findings, we will design and test therapeutic strategies to overcome resistance in vivo. We will also confirm that these resistance mechanisms are clinically relevant by evaluating resistant tumor specimens from patients. Taken together, these studies will enable the rational selection of subsequent, or second-line, treatments for patients who relapse on crizotinib based on the identified mechanism of resistance. These basic studies will therefore translate into new therapeutic approaches in the clinic that provide long lasting and meaningful benefit to our patients.

Public Health Relevance

Lung cancer is the leading cause of cancer-related deaths. For some patients, the ALK targeted therapy crizotinib is highly effective, but remissions are short-lived. Here, we will determine how ALK-positive cancers become resistant to crizotinib in order to develop new treatments that will improve the lives of patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA164273-01
Application #
8221301
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2012-02-20
Project End
2016-12-31
Budget Start
2012-02-20
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$353,463
Indirect Cost
$145,963
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Shaw, Alice T; Gandhi, Leena; Gadgeel, Shirish et al. (2016) Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17:234-42
Gainor, Justin F; Dardaei, Leila; Yoda, Satoshi et al. (2016) Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 6:1118-1133
Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S W et al. (2016) Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 17:452-63
Gainor, Justin F; Chi, Andrew S; Logan, Jennifer et al. (2016) Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib. J Thorac Oncol 11:256-60
Gainor, Justin F; Shaw, Alice T; Sequist, Lecia V et al. (2016) EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22:4585-93
Dagogo-Jack, Ibiayi; Gainor, Justin F; Porter, Rebecca L et al. (2016) Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping. J Thorac Oncol 11:1522-8
Shaw, Alice T; Friboulet, Luc; Leshchiner, Ignaty et al. (2016) Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med 374:54-61
Lin, Jessica J; Shaw, Alice T (2016) Resisting Resistance: Targeted Therapies in Lung Cancer. Trends Cancer 2:350-364
Katayama, Ryohei; Kobayashi, Yuka; Friboulet, Luc et al. (2015) Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. Clin Cancer Res 21:166-74
Katayama, Ryohei; Lovly, Christine M; Shaw, Alice T (2015) Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res 21:2227-35

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