ERK Hyperactivation Serves as a Unified Mechanism of Escape in Intrinsic and Acquired CDK4/6 Inhibitor Resistance in Acral Lentiginous Melanoma

Abstract

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in > 60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression are a unified mechanism of both intrinsic and acquired CDK4i/6i resistance. MEK and/or ERK inhibition increases CDK4i/6i efficacy in a patient-derived xenograft (PDX) model of ALM and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach to improve outcomes for patients with advanced ALM.

Single-cell RNA sequencing unveils tumor heterogeneity and immune microenvironment between subungual and plantar melanoma

“…A study of 514 acral melanomas revealed that alterations in the CDK4 pathway were frequent and that these alterations promoted G1 to S cell cycle transition and tumor progression 15 . Recent studies have shown that combination treatment of CDK4/6 plus MEK inhibitors as first- and second-line therapy in patients with advanced AM 16 . Besides, we found that SM is higher CNV signal and lower T/NK cells, which suggests that SM may have strong characteristics of invasiveness and metastasis and have a worse prognosis, in agreement with the study of Holman BN et al 8 .…”

Single-cell RNA sequencing unveils tumor heterogeneity and immune microenvironment of acral melanoma

“…A study of 514 acral melanomas revealed that alterations in the CDK4 pathway were frequent and that these alterations promoted G1 to S cell cycle transition and tumor progression (Kong et al 2017). Recent studies have shown that combination treatment of CDK4/6 plus MEK inhibitors as rst-and second-line therapy in patients with advanced AM (Rebecca et al 2023). Besides, we found that SM is higher CNV signal and lower T/NK cells, which suggests that SM may have strong characteristics of invasiveness and metastasis and have a worse prognosis, in agreement with the study of Holman BN et al (Holman et al 2020).…”