00085472can143358-sup-140846_2_supp_3187033_nwffwd.ppt (433 kB)

Supplementary Figure 7 from Maximizing the Efficacy of MAPK-Targeted Treatment in PTEN^LOF/BRAF^MUT Melanoma through PI3K and IGF1R Inhibition

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posted on 2023-03-30, 23:43 authored by Barbara Herkert, Audrey Kauffmann, Sandra Mollé, Christian Schnell, Thomas Ferrat, Hans Voshol, Janina Juengert, Hélène Erasimus, Grégory Marszalek, Malika Kazic-Legueux, Eric Billy, David Ruddy, Mark Stump, Daniel Guthy, Mitko Ristov, Keith Calkins, Sauveur-Michel Maira, William R. Sellers, Francesco Hofmann, Michael N. Hall, Saskia M. Brachmann

Concomitant inhibition of PI3Kβ, IGF1R and MAPK signaling are leading to induction of cell death. A) Effects of treatment with the indicated inhibitors as single-agents in RVH-421 were evaluated by immunoblotting using phospho-specific or total target protein antibodies. B) Fractions of living (A-/PI-), necrotic (A-/PI+), early (A+/PI-) and late (A+/PI+) apoptotic cells was measured upon treatment of A101D and C32 with the indicated compounds for 72h. Data are represented as mean ({plus minus}SD) of triplicates. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, IGF1Ri=AEW541, panPI3Ki=GDC0941, BRAFi=LGX818, MEKi=MEK162

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ARTICLE 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.