Abstract 2665: Biochemical inhibition profiles of 370 wild type human kinases provide a basis for selecting alternative combinations of EGFR and VEGFR inhibitors

Media type: E-Article

Title: Abstract 2665: Biochemical inhibition profiles of 370 wild type human kinases provide a basis for selecting alternative combinations of EGFR and VEGFR inhibitors

Contributor: Coussens, Nathan P.; Dexheimer, Thomas S.; Silvers, Thomas; Uzelac, Shannon; Georgius, Kyle; Carter, John; Shearer, Tia; Rao, Rekha; Gray, Karen; Srivastava, Apurva K.; Kinders, Robert J.; Evrard, Yvonne A.; Hollingshead, Melinda G.; Morris, Joel; Moscow, Jeffrey A.; Parchment, Ralph E.; Teicher, Beverly A.; Doroshow, James H.

imprint: American Association for Cancer Research (AACR), 2023

Language: English

DOI: 10.1158/1538-7445.am2023-2665

ISSN: 1538-7445

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: Abstract Drug combinations targeting the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR) have been used to treat EGFR-expressing cancers. In addition, we observed that the combination of the EGFR inhibitor erlotinib and the VEGFR2 inhibitor cediranib had greater activity in patient-derived xenografts (PDX) from rare cancers compared to the single agents alone. To better understand the combination activity and seek potential alternatives for each drug, their inhibition of 370 wild type human kinases was measured with a biochemical enzymatic assay. The single agents and combinations were tested at the IC50 value for their primary targets, 500 nM as a common reference concentration, and Cmax as achievable clinical concentrations. At the clinical Cmax, cediranib (148 nM) inhibited 5 kinases, including VEGFR2, by &gt;90% and inhibited EGFR by 75%. Erlotinib (clinical Cmax 3.15 µM) inhibited 9 kinases, including EGFR, by ≥89% and inhibited VEGFR2 by 82%. When combined at their clinical concentrations (Cmax), cediranib + erlotinib inhibited 18 kinases by ≥89%. Kinase inhibition profiles were measured for 7 agents that were candidate alternatives for cediranib or erlotinib, including: vandetanib, erdafitinib, axitinib, lenvatinib, cabozantinib, poziotinib, and mobocertinib (note: Cmax values varied 58-fold among the drugs). At clinical Cmax, cediranib showed the greatest similarity to axitinib and lenvatinib based on their kinase inhibition profiles, whereas erlotinib showed the greatest similarity to poziotinib and vandetanib. The rank order of drug similarities based on biochemical kinase inhibition profiles aligned with the NCI-60 cell-based activities of the drugs according to a COMPARE Analysis. The Bliss independence model was used to calculate the combination activity of cediranib + erlotinib from single agent data for comparison with the experimental results of the drug combination. The high correlation between the calculated and experimental datasets indicated that the model could be used to assess other drug combinations from single agent data. Comparisons of the calculated kinase inhibition profiles of the novel drug combinations to the profile of cediranib + erlotinib indicated that erlotinib would be difficult to replace; however, cediranib might be substituted by either lenvatinib or axitinib. Similarities in the activities of erlotinib in combination with cediranib, lenvatinib and axitinib were observed in complex spheroids containing patient-derived cells as well as PDX models. These results suggest that the additive effect of VEGFR inhibition on erlotinib activity may not solely be due to erlotinib’s EGFR inhibitory activity, and therefore may not be seen with other EGFR inhibitors. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Nathan P. Coussens, Thomas S. Dexheimer, Thomas Silvers, Shannon Uzelac, Kyle Georgius, John Carter, Tia Shearer, Rekha Rao, Karen Gray, Apurva K. Srivastava, Robert J. Kinders, Yvonne A. Evrard, Melinda G. Hollingshead, Joel Morris, Jeffrey A. Moscow, Ralph E. Parchment, Beverly A. Teicher, James H. Doroshow. Biochemical inhibition profiles of 370 wild type human kinases provide a basis for selecting alternative combinations of EGFR and VEGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2665.

Access State: Open Access

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