Abstract IA15: Strategies to overcome acquired resistance to kinase inhibitors

Current therapies for oncogenic kinase-driven cancers often involve kinase inhibitors. While the efficacy of these therapies is often striking, eventual relapse due to acquired resistance is common.

For example, first-generation BRAF inhibitors are making a major impact on the disease-course in BRAF-mutant cancers and metastatic melanoma in particular. Nonetheless, many patients relapse and relapsed tumors generally display BRAF pathway re-activation. In order to improve the durability and tolerability of therapy, Plexxikon has been pursuing multiple strategies. Since the well-documented RAF inhibitor paradox is implicated as a contributor to drug resistance as well as unwanted side effects, we have designed a series of compounds that exhibit potent anti-BRAF efficacy without causing paradoxical pathway activation in RAS mutant cells. These compounds, dubbed Paradox Breakers, are also active against certain BRAF isoforms that are resistant to inhibition by first-generation compounds. Furthermore, we believe that macrophages in the tumor microenvironment are likely to enable resistance to BRAF inhibition. Therefore, we are pursuing studies to co-target BRAF in tumors and macrophages in the tumor microenvironment.

Furthermore, inhibiting oncogenic KIT mutations is a validated therapeutic approach to treat gastrointestinal stromal tumors (GIST). The use of clinically approved kinase inhibitors such as imatinib frequently reveals secondary or acquired mutations that render these first-generation KIT inhibitors ineffective. Some of the acquired mutations reside in exon 17, coding for amino acids in the activation loop of the folded protein. This set of mutations has been shown to constitutively activate the receptor. Using a scaffold-based drug discovery approach, we have successfully identified a novel KIT exon 17 mutant-targeted inhibitor that shows minimal cross-reactivity in a kinome wide screen. This inhibitor shows robust efficacy in a patient-derived, imatinib-resistant GIST xenograft (Molecular Response).

Plans to develop these approaches into clinical projects will be discussed.

Citation Format: Gideon Bollag (on behalf of the Plexxikon team). Strategies to overcome acquired resistance to kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA15.