In the U.S. alone during 2021, an estimated 106,110 and 101,280 people will be diagnosed with invasive and non-invasive (in situ) melanoma, respectively. Moreover, it is expected that 7,180 people will die from melanoma in 2021 and metastatic melanoma will be responsible for the vast majority of those deaths. In addition, invasive melanoma incidence rates have recently increased by ~2% per year.

To design therapeutic strategies and cure melanoma, we will need to identify the mechanisms that drive the disease. Mutations in genes associated with cell proliferation cause cancer. In melanoma, BRAF is the most frequently mutated gene, causing over 50% of all melanoma cases. Active BRAF mutations over-activate cyclin dependent kinase 4 and 6 (CDK4/6) to initiate cell proliferation, thus leading to the abnormal cell growth. Indeed, CDK4/6 inhibitor-based therapies have shown promising preclinical and clinical outcomes and are superior to the standard BRAF/MEK inhibitor therapy for treating metastatic melanoma harboring BRAF mutations. However, drug resistance severely limits the success of CDK4/6 inhibitor-based therapies. Here we propose to study the underlying molecular mechanisms of resistance to CDK4/6 inhibitors. Furthermore, our interdisciplinary team will evaluate the therapeutic effect of our new strategy for overcoming resistance.

Elucidating the molecular mechanisms behind drug resistance is challenging given the rarity of resistant cells, tumor heterogeneity, and plasticity of individual cancer cells. Current methods based on bulk analysis of tumor cell populations are insufficient to address how small subsets of melanoma cells can develop resistance to CDK4/6 inhibitors. By tracking thousands of cells at the single-cell level over multiple days, our strategy allows us to 1) isolate individual cells developing drug resistance and 2) monitor key steps to determine when and how subsets of cells develop drug resistance. Using these cutting-edge approaches, we will elucidate how drug-resistant cells differ from non-resistant cells and how these phenotypes contribute to CDK4/6 inhibitor resistance in BRAF-mutant melanoma.

Outcomes from this proposal will provide new insights into the molecular mechanism underlying resistance and new therapeutic strategies to overcome resistance to CDK4/6 inhibitors in melanoma. This collaboration between basic and translational investigators has the potential to advance novel drug combinations into human clinical trials that will first focus on BRAF-mutant melanoma. If successful, we anticipate that our approach might be relevant for other types of melanoma and potentially other types of cancer.