Cutaneous melanoma, a malignancy originating from melanocytes in the skin, is challenging to treat due to its aggressive nature and propensity to metastasize.

NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

Phosphatidylinositol‐3'‐kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3' hydroxyl (OH) of the inositol ring of phosphatidylinositides (PI). Through their downstream effectors, PI3K generated lipids (PI3K‐lipids hereafter) such as PI(3,4,5)P₃ and PI(3,4)P₂ regulate myriad biochemical and biological processes in both normal and cancer cells including responses to growth hormones and cytokines; the cell division cycle; cell death; cellular growth; angiogenesis; membrane dynamics; and autophagy and many aspects of cellular metabolism. Engagement of receptor tyrosine kinase by their cognate ligands leads to activation of members of the Class I family of PI3'‐kinases (PI3Kα, β, δ & γ) leading to accumulation of PI3K‐lipids. Importantly, PI3K‐lipid accumulation is antagonized by the hydrolytic action of a number of PI3K‐lipid phosphatases, most notably the melanoma suppressor PTEN (lipid phosphatase and tensin homologue). Downstream of PI3K‐lipid production, the protein kinases AKT1‐3 are believed to be key effectors of PI3'‐kinase signalling in cells. Indeed, in preclinical models, activation of the PI3K→AKT signalling axis cooperates with alterations such as expression of the BRAF^V600E oncoprotein kinase to promote melanoma progression and metastasis. In this review, we describe the different classes of PI3K‐lipid effectors, and how they may promote melanomagenesis, influence the tumour microenvironment, melanoma maintenance and progression to metastatic disease. We also provide an update on both FDA‐approved or experimental inhibitors of the PI3K→AKT pathway that are currently being evaluated for the treatment of melanoma either in preclinical models or in clinical trials.

Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 and 3 (AKT1–3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven to be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition of AKT1–3 in melanoma cells. Although pharmacological inhibition was without effect, genetic silencing of all three AKT paralogs significantly induced melanoma cell death through effects on mTOR. This phenotype was rescued by exogenous AKT1 expression in a kinase-dependent manner. Pharmacological inhibition of PI3K and mTOR with a novel dual inhibitor effectively suppressed melanoma cell proliferation in vitro and inhibited tumor growth in vivo. Furthermore, this single-agent–targeted therapy was well-tolerated in vivo and was effective against MAPK inhibitor–resistant patient-derived melanoma xenografts. These results suggest that inhibition of PI3K and mTOR with this novel dual inhibitor may represent a promising therapeutic strategy in this disease in both the first-line and MAPK inhibitor–resistant setting.

Since its discovery more than a quarter century ago, PTEN has emerged as one of the most potent tumor suppressors and its loss of function is common to numerous cancer types including glioblastoma, prostate cancer, small cell lung cancer, and melanoma. PTEN is a lipid and protein phosphatase that contributes to various cellular processes, primarily by regulating key signaling pathways. Extensive research over the past two decades has uncovered many aspects of PTEN regulation and function and highlighted the role of PTEN in tumor suppression. PTEN loss‐of‐function is associated with the progression of a substantial portion of melanoma cases, and while its role in melanoma suppression is often ascribed to its inhibition of the PI3K/AKT signaling pathway, recent studies may hint at a more complex role for PTEN in melanoma. In this review, we provide an overview of how PTEN suppresses melanomagenesis.