ERK Hyperactivation Serves as a Unified
Mechanism of Escape in Intrinsic and Acquired
CDK4/6 Inhibitor Resistance in Acral Lentiginous
Melanoma
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.
Our Greatest Hits
Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance
Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.
Genetic characteristics and response to systemic therapies of acral lentiginous melanoma at a tertiary care center-a retrospective review
Acral lentiginous melanoma (ALM) is an aggressive subtype of cutaneous malignant melanomas that accounts for 50-80% of melanomas in ethnic minorities. Studies on the genetic profile of these tumors largely result from cohorts in Europe, Asia, and Latin America, few inclusive of Black patients.
Of the 93 patients identified, 62.4% were Caucasian, 25.8% Black, 4.30% Hispanic, 4.30% Asian, and 3.22% identified as other. Fourteen of 17 patients receiving targeted or immunologic agents experienced disease progression during treatment, including all patients with a BRAF V600E mutation.
​Response to targeted and immunologic therapies in ALM patients was overwhelming poor, particularly in BRAF V600E-mutated tumors in contrast to the positive prognosis associated with BRAF V600E mutations in other advanced cutaneous melanoma subtypes.
Un-Fair Skin: racial disparities in acral melanoma research
Patients of colour predominately present with acral lentiginous melanoma (ALM), the most lethal subtype of cutaneous melanoma. We here advocate for increased mechanistic studies using models derived from the patient communities suffering most from ALM to develop therapies that benefit patients across all ethnic and racial groups.