Abstract
Kinase inhibitors form the largest class of precision medicine. From 2013 to 2017, 17 have been approved, with 8 different mechanisms. We present a comprehensive profiling study of all 17 inhibitors on a biochemical assay panel of 280 kinases and proliferation assays of 108 cancer cell lines. Drug responses of the cell lines were related to the presence of frequently recurring point mutations, insertions, deletions, and amplifications in 15 well-known oncogenes and tumor-suppressor genes. In addition, drug responses were correlated with basal gene expression levels with a focus on 383 clinically actionable genes. Cell lines harboring actionable mutations defined in the FDA labels, such as mutant BRAF(V600E) for cobimetinib, or ALK gene translocation for ALK inhibitors, are generally 10 times more sensitive compared with wild-type cell lines. This sensitivity window is more narrow for markers that failed to meet endpoints in clinical trials, for instance CDKN2A loss for CDK4/6 inhibitors (2.7-fold) and KRAS mutation for cobimetinib (2.3-fold). Our data underscore the rationale of a number of recently opened clinical trials, such as ibrutinib in ERBB2- or ERBB4-expressing cancers. We propose and validate new response biomarkers, such as mutation in FBXW7 or SMAD4 for EGFR and HER2 inhibitors, ETV4 and ETV5 expression for MEK inhibitors, and JAK3 expression for ALK inhibitors. Potentially, these new markers could be combined to improve response rates. This comprehensive overview of biochemical and cellular selectivities of approved kinase inhibitor drugs provides a rich resource for drug repurposing, basket trial design, and basic cancer research.
Highlights
The theory of "oncogene addiction" postulates that, despite the diverse array of genetic lesions typical of cancer, some tumors rely on one single dominant oncogene for growth and survival [1]
Well-known examples include the EGFR kinase inhibitor gefitinib to treat lung cancers with activating mutations in EGFR [2], inhibitors of mutant BRAF (V600E) for metastatic melanoma [3], or anaplastic lymphoma kinase (ALK) inhibitors to treat lung cancers characterized by transforming ALK translocations [4]
We profiled 17 small-molecule kinase inhibitors (Table 1) that have been approved by the FDA in the past 4 years on a panel of 280 biochemical kinase assays and a cell panel of 108 human cancer lines derived from various tumor tissues (Oncolines; ref. 13; Table 1)
Summary
The theory of "oncogene addiction" postulates that, despite the diverse array of genetic lesions typical of cancer, some tumors rely on one single dominant oncogene for growth and survival [1]. We profiled 17 small-molecule kinase inhibitors (Table 1) that have been approved by the FDA in the past 4 years (from November 2013 to May 2018) on a panel of 280 biochemical kinase assays and a cell panel of 108 human cancer lines derived from various tumor tissues This follows up on an earlier study in which we profiled all kinase inhibitors approved prior to November 2013 [14]. Our study provides unique insight into the relationship between biochemical and specific cellular responses of approved targeted therapy, and opens opportunities for wider application
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