Targeted therapies in cutaneous melanoma

PROJECT SUMMARY
The incidence of cutaneous melanoma is rising. While targeted inhibitors and immune checkpoint
antibodies have increased long-term survival in advanced-stage cutaneous melanoma, many
patients still do not benefit and regimens are associated with significant toxicities. We are studying
the determinants of treatment response and mechanisms of resistance in melanoma. From our
studies, we aim to provide pre-clinical data for new combinations that delay/prevent the onset of
acquired resistance while minimizing patient toxicities in order to improve patient survival and
quality of life. Multiple clinical trials have emanated from our work (NCT03580382, NCT02012231,
NCT02683395). Aberrant cell cycle regulation is a hallmark feature of cancer. In melanoma, cell
cycle progression is promoted through mutations in BRAF, NRAS and NF1 leading to MEK-ERK1/2
pathway activation, amplification of cyclins and/or cyclin-dependent kinases (CDK) and/or loss of
CDK inhibitor proteins. Selective CDK4/6 inhibitors are FDA-approved in ER-positive/HER2-
negative breast cancer but their use in melanoma requires optimization of combinations and
schedules. We aim to understand how to utilize CDK4/6 inhibitors in melanoma and combine them
with immune checkpoint agents, which remove the blocks on T cell action. In the previous cycle of
funding, we provided new insights into mechanisms of acquired resistance to BRAF inhibitor
monotherapy and combination therapy. We then developed novel models and to analyze
resistance to BRAF pathway inhibitors and CDK4/6 inhibitor-based combinations. We identified
enhanced phosphorylation of S6 as a common node of therapy resistance and validated our
studies using patient trial samples. In this current proposal, we aim to identify and target
mechanisms underlying residual disease following CDK4/6 inhibitor + MEK inhibitor treatment in
melanoma. Additionally, we aim to determine effects of CDK4/6 inhibitor + MEK inhibitor on the
tumor immune microenvironment. The application will utilize novel models and patient samples
from relevant clinical trials to measure heterogeneity of tumors and mechanisms of drug tolerance
and resistance to CDK4/6 inhibitor + MEK inhibitor. Identifying the tumor intrinsic mechanisms and
effects on the tumor-associated immune microenvironment will inform potential new treatment
strategies across genetic subset of cutaneous melanoma.

Grant Number: 5R01CA182635-10
NIH Institute/Center: NIH
Principal Investigator: Andrew Aplin