Tumor exome sequencing and copy number alterations reveal potential predictors of intrinsic resistance to multi-targeted tyrosine kinase inhibitors

• Published in: Oncotarget Vol. 8; no. 70; pp. 115114 - 115127
• Main Authors: Gillis, Nancy K., Rotroff, Daniel M., Mesa, Tania E., Yao, Jiqiang, Chen, Zhihua, Carulli, Michael A., Yoder, Sean J., Walko, Christine M., Teer, Jamie K., McLeod, Howard L.
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 29.12.2017
• Subjects: Research Paper; tyrosine kinase inhibitors; somatic genetics; copy number; intrinsic; resistance
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22914

Multi-targeted tyrosine kinase inhibitors (TKIs) have broad efficacy and similar FDA-approved indications, suggesting shared molecular drug targets across cancer types. Irrespective of tumor type, 20-30% of patients treated with multi-targeted TKIs demonstrate intrinsic resistance, with progressive disease as a best response. We conducted a retrospective cohort study to identify tumor (somatic) point mutations, insertion/deletions, and copy number alterations (CNA) associated with intrinsic resistance to multi-targeted TKIs. Using a candidate gene approach (n=243), tumor next-generation sequencing and CNA data was associated with resistant and non-resistant outcomes. Resistant individuals (n=11) more commonly harbored somatic point mutations in , , , and and CNA in , , and compared to non-resistant (n=26, p<0.01). Using a random forest classification model for variable reduction and a decision tree classification model, we were able to differentiate intrinsically resistant from non-resistant patients. CNA in and were the most important analytical features, implicating the cyclin D pathway as a potentially important factor in resistance to multi-targeted TKIs. Replication of these results in a larger, independent patient cohort has potential to inform personalized prescribing of these widely utilized agents.