2009 UALC
Susumu Kobayashi, MD
Beth Israel Deaconess Medical Center
Research Project:
Targeting EML4-ALK in non-small cell lung cancer: Identification of resistance to ALK inhibitors
Summary:
ALK inhibitors have recently been show to be very effective in treating patients harboring ALK mutations. However, like EGFR tyrosine kinase inhibitors (TKIs), ALK TKIs can also result in acquired resistance. Dr. Kobayashi is investigating the mechanisms of resistance to ALK inihibitors (crizotinib / Xalkori) using cell lines and samples from patients being treated with ALK TKIs.
More Content:
Final Report
As expected Dr. Kobayashi found that the EML4-ALK fusion was necessary to be responsive to crizotinib. He generated a resistant cell line, but was unable to isolate specific secondary mutations in EML4-ALK, activation of other tyrosine kinases, or secondary mutations working in collaboration with Dr. Matthew Meyerson and the Broad Institute. Although no additional mutations were detected, they found several small amplifications/deletions in the resistant cell line. In addition, Dr. Kobayashi worked with patients who were ALK positive and treated with crizotinib. All patients showed major clinical responses, and thus far, three patients became resistant to crizotinib. Potential mechanisms of resistance were identified as a novel deletion of the ALK protein in one patient. Because ALK mutation does not appear to be a major cause of resistance, Dr. Kobayashi is investigating the novel deletion as a mechanism. He has created a model system to study this deletion, and is pursuing additional mechanisms of resistance through his collaboration with the Broad Institute.
Notable Accomplishments
Dr. Kobayashi has published his work in the Journal of Clinical Oncology and The Journal of Thoracic Oncology. Dr. Kobayashi was awarded $50,000 from the Dana Farber Cancer Institute / Harvard Cancer Center to continue this project. His team was also awarded the 2010 Team Science Award from the American Association of Cancer Research.