Kinase inhibitors have become important therapeutic agents with at least 27 FDA-approved compounds currently available. While this success has brought important benefit to cancer patients, new challenges have been revealed. In particular, resistances to therapy and novel therapy-induced side effects have introduced rationale for optimizing next-generation treatment regimens. Two specific examples will be discussed: RAF and KIT inhibitors for BRAF- and KIT-driven cancers.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting MAPK pathway signaling independent of RAS activation. Efforts to develop agents to block mutated BRAF have brought substantial therapeutic improvement in personalized treatment of metastatic melanoma. Nonetheless, many patients relapse and relapsed tumors generally display MAPK pathway re-activation. The development of these agents also revealed an unexpected consequence of these targeted therapies: stimulated growth of certain cancers. Structurally-diverse ATP-competitive RAF kinase inhibitors can either inhibit or paradoxically activate the MAPK pathway depending whether the pathway is activated by a BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. We have identified next generation RAF inhibitors (dubbed “paradox breakers”) that inhibit mutant RAF cells without activating the MAPK pathway in cells containing an upstream activation event. These new inhibitors maintain efficacy in BRAF-driven cell and animal models. In addition, PLX8394 is able to overcome several known mechanisms of resistance to first generation RAF inhibitors. By dissociating MAPK pathway inhibition from pathway activation, the next generation RAF inhibitors may yield both improved safety and more durable efficacy than first generation RAF inhibitors.

KIT inhibitors are now standard therapy for advanced gastrointestinal stromal tumors, and indeed comprise 1st, 2nd and 3rd line treatments reflecting both the marked dependence of these tumors on KIT and also the facile development of resistance. Even with multiple compounds approved, resistance mutations - in exon 17 in particular - still limit the durability of clinical benefit. We have discovered PLX9486 as an effective inhibitor of mutant KIT, including exon 17 mutations, with the added feature of selectivity versus the wild-type KIT kinase activity. This compound shows potent activity against exon 17 mutant tumors both in vitro and in vivo. Anticipating the obstacle of polyclonal KIT mutations in standard TKI-resistant patients, clinical development plans include a study combining PLX9486 with PLX3397, a potent KIT inhibitor addressing complementary KIT mutational profiles.

Citation Format: Gideon Bollag. Optimizing kinase inhibitors to treat cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA32.