The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma

Abstract

Stimulation of the c-Kit receptor tyrosine kinase has a critical role in the development and migration of melanocytes, and oncogenic c-Kit mutants contribute to the progression of some melanomas. c-Kit signalling activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and their relative contribution to the activities of oncogenic and ligand-dependent c-Kit remains uncertain. We show that PI3K is a major regulator of MAPK activation in response to c-Kit activity and the dominant effector of c-Kit-driven melanocyte proliferation and melanoma survival. Nevertheless, inhibition of the PI3K pathway in c-Kit mutant melanoma cells did not replicate the apoptotic efficacy of the c-Kit inhibitor, imatinib mesylate. Instead, the simultaneous suppression of the PI3K and MAPK pathways promoted a strong synergistic apoptotic effect. These data indicate that MAPK functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Thus, the concurrent inhibition of PI3K and MAPK signalling is required to suppress oncogenic c-Kit activity and may provide an effective therapeutic strategy in c-Kit mutant melanomas.

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

“…About 22% of triple-wild-type melanomas contain KIT aberrations (7). Constitutive activation of C-KIT, via KIT mutation or amplification, leads to the coactivation of downstream RAS/MAPK and PI3K/AKT/mTOR pathways and subsequent promotion of tumorigenesis (8). Current therapeutic strategies for treating KIT-aberrant melanomas include tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib (5).…”

Oncogene-Directed Small Molecule Inhibitors for the Treatment of Cutaneous Melanoma

“…It has been shown that oncogenic KIT-driven melanomagenesis employs MAPK as a redundant survival pathway to strengthen PI3K signaling, and that cell death requires combined inhibition of both pathways [81]. Interest in therapeutically targeting KIT led to imatinib being the first KIT inhibitor tested in melanoma, with initially disappointing results [76,80].…”

Role of c-Kit in the growth, migration and differentiation of human cardiac progenitor cells.

“…Studies on SCF mediated c-kit activation in mast cells, endothelial cells and melanocytes [59,99,119,120] have shown that this is an important pathway regulating genes that are involved in cell survival, proliferation, migration and differentiation. There are four major classes of PI3Ks and the Class I is further divided into class IA and IB.…”

“…It has been reported that these two pathways are dependent on each other and the inhibition of the PI3K-AKT pathway leads to the inhibition of the MEK-ERK pathway, at least in melanocytes [120]. In the same cells, inhibition of these two pathways with pharmacological inhibitors has resulted in cellular apoptosis, indicating the indispensable role of the above two pathways in cell survival [120].…”

“…They are identified to play an important role in regulating the proliferation, migration and survival in melanocytes [36,194], mast cells [139,195], endothelial cells [59] and hematopoietic stem cells [196]. It has been reported that these two pathways are dependent on each other and the inhibition of the PI3K-AKT pathway leads to the inhibition of the MEK-ERK pathway, at least in melanocytes [120]. In the same cells, inhibition of these two pathways with pharmacological inhibitors has resulted in cellular apoptosis, indicating the indispensable role of the above two pathways in cell survival [120].…”