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 #
5R01CA164273-02
Application #
8431743
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
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$330,727
Indirect Cost
$135,677
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Gainor, Justin F; Sherman, Carol A; Willoughby, Kathryn et al. (2015) Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 10:232-6
Friboulet, Luc; Li, Nanxin; Katayama, Ryohei et al. (2014) The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662-73
Katayama, Ryohei; Friboulet, Luc; Koike, Sumie et al. (2014) Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 20:5686-96
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Arteaga, Carlos L; Engelman, Jeffrey A (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303

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