Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

Abstract

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.

Overcoming resistance to BRAF inhibitors

“…While in vitro studies clearly show the potential of using AKT, pan-PI3K or dual PI3K/mTOR inhibitors in combination with BRAF/MEK inhibitor, the translation into the clinical setting is troublesome due to enhanced systemic toxicities (124)(125)(126)(127)(128). The PI3K family of proteins is relevant in many physiological processes and malignant conditions but nevertheless this interest on the pathway is producing encouraging data advancing in the understanding of melanoma specific PI3K-signaling (129) and lately PI3Kβ isoform specific inhibitors are being developed and trialed in the context of PTEN mutant melanoma patients (130)(131)(132). Interestingly targeting the PI3K has not only been proposed as a strategy to overcome resistance to BRAF/MEK inhibitors, but also with the therapeutic goal of preventing the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma (133).…”

Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling

“…pathway is also relevant to the development of melanoma [31][32][33][34]. Therefore, SIRT6 may regulate autophagy via the IGF-AKT pathway in melanoma.…”

Bis-anthracycline WP760 abrogates melanoma cell growth by transcription inhibition, p53 activation and IGF1R downregulation

“…The IGF1R pathway was reported to be involved in melanocyte transformation [ 22 ], aggressiveness and stemness [ 23 , 24 ] as well as therapy resistance [ 25 ]. Targeting of the IGF1R pathway exerts potent anticancer effects [ 26 , 27 ] and combined inhibition of MAPK, PI3K, and IGF1R successfully inhibited melanoma growth and overcame resistance of melanoma cells harboring BRAF and PTEN mutations [ 28 ]. Here, we also observed that cell lines, both BRAF- and PTEN-mutated, were the most sensitive towards WP760, however further studies are required to prove that inhibition of IGF1R indeed contributes to WP760 anti-melanoma activity.…”