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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Massachusetts General Hospital
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Lin, Jessica J; Zhu, Viola W; Schoenfeld, Adam J et al. (2018) Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC. J Thorac Oncol 13:1530-1538
Lin, Jessica J; Jiang, Ginger Y; Joshipura, Nencyben et al. (2018) Efficacy of Alectinib in Patients with ALK-Positive NSCLC and Symptomatic or Large CNS Metastases. J Thorac Oncol :
Dagogo-Jack, Ibiayi; Brannon, A Rose; Ferris, Lorin A et al. (2018) Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA. JCO Precis Oncol 2018:
Yoda, Satoshi; Lin, Jessica J; Lawrence, Michael S et al. (2018) Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov 8:714-729
Dardaei, Leila; Wang, Hui Qin; Singh, Manrose et al. (2018) SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med 24:512-517
Lin, Jessica J; Zhu, Viola W; Yoda, Satoshi et al. (2018) Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer. J Clin Oncol 36:1199-1206
Gainor, Justin F; Tseng, Diane; Yoda, Satoshi et al. (2017) Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer. JCO Precis Oncol 2017:
Dagogo-Jack, Ibiayi; Fabrizio, David; Lennerz, Jochen et al. (2017) Circulating Tumor DNA Identifies EGFR Coamplification as a Mechanism of Resistance to Crizotinib in a Patient with Advanced MET-Amplified Lung Adenocarcinoma. J Thorac Oncol 12:e155-e157
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