Determination of autophagy modulation upon CDK4/6 inhibition and ERK hyperactivation in acral melanoma

Abstract

Melanoma arises from melanocytes transformed from the basal lamina of the dermal-epidermal junction and harbor a remarkable proliferation, metastasis, and immune evasion capacity propelling a patient's poor prognosis. Among other types of melanomas, acral lentiginous melanoma (ALM) is a rare subtype that appears in the palm, soles, and nail bed areas, most in non-white patients. Regardless of ALM social disparities complicators that boost the worst prognosis, ALM patients do not bring a gene mutation profile similar to other common melanoma types, consequently not responding adequately to standard-of-care targeted therapies. In this context, the genetic profile of ALM patient tumor tissue identified cyclin-dependent kinase 4 (CDK4)-pathway alterations in 53-82% of ALM cases as a predictor of shorter patient overall survival and a platform for anti-CDK4/6 therapy development. However, in recent clinical trials, the median progression-free survival (PFS) was barely 2.2 months showing that most patients did not benefit from CDK4/6 inhibition (CDK4i/6i). Furthermore, new data from Professor Dr. Vito Rebecca's group at Johns Hopkins University (not published yet) identified hyperactivation of the MAPK pathway and elevated cyclin D1 as functional drivers of intrinsic/acquired CDK4i/6i resistance phenotype. This scenario suggests that clinical MEK inhibitor trametinib can be associated with CDK4i/6i to overcome this specific resistant phenotype in ALM cancer. Nonetheless, recent studies have shown that CDK4i/6i can trigger another resistant phenotype pathway related to metabolism switching through autophagy induction or lysosomal mediated disruption with different responses depending on the type of cancer cells. Since autophagy modulation is a melanoma-related resistance phenotype mechanism and the relationship between CDK4i/6i in ALM cell were not elucidated, this current project aims to understand the mechanisms of cellular resistance behind CDK4i/6i activity and autophagy modulation in ALM. (AU)