American Association for Cancer Research
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Supplementary Figure 8 from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M

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journal contribution
posted on 2023-04-03, 20:21 authored by Ho-June Lee, Gabriele Schaefer, Timothy P. Heffron, Lily Shao, Xiaofen Ye, Steve Sideris, Shiva Malek, Emily Chan, Mark Merchant, Hank La, Savita Ubhayakar, Robert L. Yauch, Valentina Pirazzoli, Katerina Politi, Jeff Settleman

PDF file - 78K, Efficacy of PKC412 on tumor growth and signaling in EGFRL858R+T790M transgenic mice.



Approximately half of EGFR-mutant non–small cell lung cancer (NSCLC) patients treated with small-molecule EGFR kinase inhibitors develop drug resistance associated with the EGF receptor (EGFR) T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M that spare wild-type EGFR. These findings show the use of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.Significance: EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers. Cancer Discov; 3(2); 168–81. ©2012 AACR.See related commentary by Brewer and Pao, p. 138This article is highlighted in the In This Issue feature, p. 125