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.
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.
|Lin, Jessica J; Ritterhouse, Lauren L; Ali, Siraj M et al. (2017) ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non-Small Cell Lung Cancer. J Thorac Oncol 12:872-877|
|Lin, Jessica J; Riely, Gregory J; Shaw, Alice T (2017) Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer Discov 7:137-155|
|Shaw, Alice T; Felip, Enriqueta; Bauer, Todd M et al. (2017) Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 18:1590-1599|
|Lin, Jessica J; Shaw, Alice T (2017) Recent Advances in Targeting ROS1 in Lung Cancer. J Thorac Oncol 12:1611-1625|
|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|
|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; 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|
|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|
|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 17:234-242|
|Lin, Jessica J; Shaw, Alice T (2016) Resisting Resistance: Targeted Therapies in Lung Cancer. Trends Cancer 2:350-364|
Showing the most recent 10 out of 38 publications