Abstract 2849: Analysis of the cancer gene targeting of clinical kinase inhibitor drugs by combining cellular and biochemical profiling
Authors: Zaman Guido J.R. , Uitdehaag Joost C.M. , Buijsman Rogier C. , Roos Jeroen A.D.M. de , Doornmalen Antoon M. van , Prinsen Martine B.W. , Man Jos de , Kawase Yusuke , Tanizawa Yoshinori , Yoshino Kohichiro 
Published: May 2015

[Purpose] Kinase inhibitors are a prime example of the success of targeted therapy. Crucial to the development of targeted therapies is the ability to couple drug response to genetic markers, such as mutations in oncogenes and/or tumor suppressors, chromosomal rearrangements, and/or gene amplifications. The efficacy of response to such markers is linked with the biochemical characteristics of kinase inhibitors. However, it is poorly understood what profiles are required to achieve the best targeting. We have systematically compared the biochemical potency and selectivity profiles of all kinase inhibitor drugs in clinical use with their ability to inhibit cell proliferation in a panel of forty-four human cancer cell lines from diverse tumor tissue origins.[Experimental procedures] Proliferation assays were established for a panel of forty-four human cancer cell lines licensed from the American Type Culture Collection. The panel represents twenty-three of the most frequently identified genetic changes in the COSMIC Cell Lines (CCL) project in at least two cell lines. We profiled all twenty-five kinase inhibitors in clinical use on the cancer cell line panel, together with a number of classic cytotoxic agents for comparison. The proliferation assay data were linked to genetic data from the CCL database by Anova and volcano plot analysis. In parallel the biochemical profiles of all twenty-five kinase inhibitor drugs were determined on a panel of 313 protein kinase enzyme activity assays. The biochemical profiling data were used to interpret the cellular targeting compounds in terms of biochemical potency, selectivity and kinase poly-pharmacology.[Results] The suitability of the cell line panel was validated by confirming the known sensitivity of mutant B-RAF to vemurafenib, of BCR-ABL to imatinib, and EGFR overexpression to erlotinib. Mutation in SMAD4 was identified as a novel drug sensitivity marker for EGFR inhibitors, while mutation in the gene for β-catenin was identified as a sensitivity marker for MEK inhibitors, such as trametinib. When comparing compounds with similar mechanisms, dabrafenib is more efficient at selectively inhibiting BRAF-mutant transformed cells than vemurafenib. Of all ABL inhibitors, imatinib has the best targeting efficacy. The compound that most selectively inhibits growth of EGFR-overexpressing cell lines, is gefitinib.[Conclusions] Cancer cell line profiling can be used to identify novel sensitivity markers of drug response. Cancer cell line profiling in combination with biochemical kinase profiling revealed biochemical selectivity and potencies as prime determinants of on target efficacy of kinase inhibitor drugs, the extent of which is target-dependent. The combination of cell panel profiling and kinome profiling is an important tool for the development of optimal targeted therapies for kinases.

Citation Format: Guido J.R. Zaman, Joost C.M. Uitdehaag, Rogier C. Buijsman, Jeroen A.D.M. de Roos, Antoon M. van Doornmalen, Martine B.W. Prinsen, Jos de Man, Yusuke Kawase, Yoshinori Tanizawa, Kohichiro Yoshino. Analysis of the cancer gene targeting of clinical kinase inhibitor drugs by combining cellular and biochemical profiling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2849. doi:10.1158/1538-7445.AM2014-2849