Targeting effector pathways in RAC1^P29S-driven malignant melanoma

Abstract

Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recently, genomic analyses revealed that 4-9% of sun-exposed melanoma bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signaling from RAC1 P29S , we here extend this analysis to examine the roles of PI3Ks and SRF/MITF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036) and certain PI3Ks inhibitors (BKM120, TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not mutant BRAF, however other PI3K inhibitors, including PI3Kα-selective inhibitors are less effective. Similar results were seen in vivo, using embryonic zebrafish development as a readout, but now including an SRF/MRTF inhibitor (CCG-203971). These results suggest that targeting Group A PAKs and/or SRF/MRTF represent promising approach to suppress RAC1 signaling in malignant melanoma.

The role of PI3'‐lipid signalling in melanoma initiation, progression and maintenance

“…One such PI3Kβ inhibitor, TGX‐221, was reported to exhibit substantial suppression of PIP 3/2 '‐lipid signalling in PTEN Null tumour cells 74,75 . However, direct examination of this question in PTEN deficient or proficient melanoma cells failed to detect a correlation between PTEN status and sensitivity to PI3Kβ inhibitors including TGX‐221 76,77 . Hence, the precise mechanism(s) by which different class I PI3K isoforms drive PTEN Null melanomas and other tumours remain to be identified 78 …”

RAC1 Activation as a Potential Therapeutic Option in Metastatic Cutaneous Melanoma

“…Regarding the PI3K network, RAC1 activates AKT by selectively interacting with PI3Kβ [ 31 ]. Considering that selective PI3Kβ inhibitors were able to prevent melanoma cell proliferation and migration driven by mutant RAC1 but not by mutant BRAF, whilst PI3Kα inhibitors had the opposite effect [ 87 ]; and restricted PI3K inhibitors activity in RAC1P29S melanocytes [ 34 ], it would be interesting to further investigate PI3K inhibitors.…”