Abstract 1480: Comparative cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020
Authors: Kooijman Jeffrey J. , van Riel Wilhelmina E. , Prinsen Martine B. , Dylus Jelle , de Roos Jeroen A. , Grobben Yvonne , Willemsen-Seegers Nicole , Muller Michelle , de Man Jos , Narumi Yugo , Kawase Yusuke , Buijsman Rogier C. , van Gerwen Suzanne J. , Zaman Guido J. 
Published: July 2021

Kinases are the major anticancer drug target class of the 21st century with nearly sixty small molecule kinase inhibitors approved for clinical use in the first two decades. While there are more than 500 kinases encoded by the human genome, currently approved inhibitors act primarily through approximately twenty different targets. Key to the success of kinase inhibitor therapy has been the simultaneous development of biomarker assays to enable the selection of patients most likely to respond. Predictive drug response biomarkers can be identified with cancer cell panel profiling, which is the parallel testing of compounds on a large panel of cancer cell lines. By correlating drug sensitivity with genomic information of the cell lines, strategies for patient stratification or drug repurposing have been developed [1-3]. In two earlier studies [2,3], we compared the kinase selectivity and the cellular inhibition profiles of all kinase inhibitors approved by the FDA until May 2018. Here, we will present the cancer cell panel profiling of all twenty small molecule kinase inhibitors approved since then. Several of these inhibitors act through well-known targets, such as ALK (lorlatinib), BRAF (encorafenib), EGFR (dacomitinib) and MEK1 (binimetinib, selumetinib). Others act through kinases for which no small molecule inhibitors have been approved before, such as CSF1R (pexidartinib), FGFR (erdafitinib, pemigatinib), c-MET (capmatinib), RET (selpercatinib, pralsetinib) and TRK (larotrectinib, entrectinib). All compounds were profiled on a panel of 102 cancer cell lines, known as Oncolines, representing a wide range of solid tumors and hematological malignancies, and harboring mutant and wild-type versions of many major cancer driver genes [3]. To determine similarities in the mechanisms underlying the anti-proliferative activity of the inhibitors, their IC50 fingerprint in the cell proliferation assays were compared by hierarchical clustering [4]. Compounds that act through the same primary kinase clustered together in this analysis. Exceptions were investigated further by profiling of additional cell lines, representing cancer gene alterations that were not present in the 102 cell line panel, such as FLT3 mutation and TRK-gene fusions, which occur in relatively small cancer patient populations. To compare the genomic targeting of kinase inhibitors acting on the same biochemical target, the cancer cell lines were classified as either “mutant” or “wild-type” for specific cancer gene alterations and were grouped per cancer gene. The relationship between drug sensitivity and cancer gene mutation status was examined. Detailed genomic biomarker analyses and comparative profiling results of novel BTK, EGFR, FGFR, FLT3 and TRK kinase inhibitors will be presented.[1] Mol Cancer Ther 2017;26:2609-17; [2] PLoS ONE 2014;9:e92146; [3] Mol Cancer Ther 2019;18:470-81; [4] Mol Cancer Ther 2016;15:3097-109

Citation Format: Jeffrey J. Kooijman, Wilhelmina E. van Riel, Martine B. Prinsen, Jelle Dylus, Jeroen A. de Roos, Yvonne Grobben, Nicole Willemsen-Seegers, Michelle Muller, Jos de Man, Yugo Narumi, Yusuke Kawase, Rogier C. Buijsman, Suzanne J. van Gerwen, Guido J. Zaman. Comparative cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1480.