Game of isoforms: PI3K β-sparing inhibitor is coming.

Abstract

Cutaneous melanoma has been at the forefront of targeted therapy breakthroughs over the last 5 years. The FDA approval of BRAF and MEK inhibitors for the treatment of late-stage, mutant V600E/K BRAF-harboring melanoma patients has been heralded due to high response rates and improvements in progression-free survival, but the durable effects of these inhibitors are limited. Alterations in the phosphoinositide 3-kinase (PI3K) pathway including inactivation of PTEN (a tumor suppressor that normally down-regulates PI3K signaling) and, less frequently, mutations in PIK3CA (the gene encoding the α isoform of the PI3K catalytic subunit) have been identified in mutant BRAF melanomas. Furthermore, PI3K pathway signaling is often up-regulated in association with resistance to mutant BRAF and/or MEK targeting agents. Despite the evidence highlighting the importance of the PI3K pathway in melanoma, initial testing of class I PI3K inhibitors in patients has not produced dramatic results. An issue for combinatorial studies is the overlapping toxicities of MAPK pathway inhibitors and PI3K-targeting agents that limits their effective dosing. A recent study from Deuker and colleagues provides important preclinical advances in this area by examining the PI3K isoform dependencies in mutant BRAF melanomas. PI3K functions as a heterodimer with a p110 catalytic subunit and a regulatory subunit. Four isoforms of p110 subunits exist: α, β, δ and γ (Jean and Kiger, 2014; Yuan and Cantley, 2008). p110α and p110β are ubiquitously expressed, whereas δ and γ isoforms display highest expression in immune cells. Importantly, isoform-selective PI3K inhibitors have been developed to target tumor dependencies and minimize toxicities in non-tumor cells. Deuker et al. utilized these selective inhibitors to determine the PI3K isoform dependency of mutationally active PI3Kα and PTEN-deficient subgroups of mutant BRAF melanomas using cell lines derived from mouse models and human patients. In vitro, PTEN-deficient lines were less sensitive to the α-isoform PI3K inhibitor, BYL719, compared to mutant H1047R PI3Kα cells. In contrast to other cancer types, in which PTEN-deficient tumors are often PI3Kβ-dependent (Wee et al., 2008), PTEN-null melanomas did not rely on PI3Kβ. Growth of PTEN-null mutant BRAF melanomas was blocked by a PI3Kα/δ/γ-targeting but β-sparing inhibitor, GDC-0032. In addition, the δ/γ inhibitor, IPI145, enhanced the effects of BYL719 suggesting involvement of the δ/γ isoforms in melanoma. PI3Kα-dependency is also suggested to be present in BRAF V600E/WT PTEN melanomas, which represent a substantial proportion of mutant BRAF melanomas, although confirmation is warranted in a larger panel of BRAF V600E/WT PTEN melanoma models. “More dramatic tumor regressions were observed in vivo with the combination of BRAF-MEK pathway and PI3K inhibitors. ” A long-term limitation to both BRAF and MEK inhibitors in melanoma is acquired drug resistance and patients who develop resistance have few second-line treatment options. In addition to up-front combination, treatment of MEK inhibitor-resistant tumors with the PI3K β-sparing inhibitor resulted in a cytostatic response. These data were generated from a single MEK inhibitor-resistant tumor. As multiple mechanisms of resistance are likely to occur, it will be important to further explore effects in cultured- and patient-derived BRAF and MEK inhibitor-resistant models. Overall, the study presented by Deuker et al., provides an important preclinical advance in targeting the PI3K pathway in both first-line combinations as well as a possible second-line salvage option for BRAF-MEK pathway resistant melanomas. These findings should propel investigation of methods to quantitatively and non-invasively measure PI3K signaling in preclinical in vivo melanoma models and to determine the most effective dosing regimens. Given the high degree of immune reactivity of melanomas and remarkable advances in immune-based therapies, other key issues will be to determine the effect of targeting PI3K on infiltration of immune cells into melanomas and the extent to which PI3K-targeting agents can be combined with immune-based therapies. Advances in mutant BRAF melanomas will lead to studies addressing the importance of PI3K isoform specific targeting in wild-type BRAF subsets of melanoma for which there is an unmet need for new therapeutic strategies.