ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling

Abstract

Abstract The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of proliferation and survival of melanoma cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in a further increase in cellular proliferation. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for tumors driven by BRAF or NRAS mutations. This study demonstrates that melanoma cells overexpressing aldehyde dehydrogenase 1A1 (ALDH1A1) displayed stem-like properties which was associated with resistance to vemurafenib and trametinib through the activation of PI3K/AKT signaling instead of MAPK axis. Inhibition of PI3K/AKT signaling rescued sensitivity to drugs. Consistently, pharmacological inhibition of ALDH1A1 activity downregulated the activation of AKT and enhanced responsiveness to vemurafenib and trametinib. We propose ALDH1A1 as a new potential target for treating MAPK inhibitor resistant melanoma.