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.
While targeted small molecule inhibitors and immune checkpoint antibodies have increased long-term survival in advanced-stage cutaneous melanoma, the majority of patients still do not benefit and many of the treatment regimens are associated with significant toxicities. This application aims to provide pre- clinical data for targeted cyclin-dependent kinase inhibitor-based combinations that will provide maximal anti-tumor efficacy while minimizing patient toxicities.
|Romano, Gabriele; Chen, Pei-Ling; Song, Ping et al. (2018) A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. Cancer Discov 8:556-567|
|Hartsough, Edward J; Kugel 3rd, Curtis H; Vido, Michael J et al. (2018) Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo. Mol Cancer Ther 17:84-95|
|Teh, Jessica L F; Aplin, Andrew E (2018) Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment. Clin Cancer Res :|
|Vido, Michael J; Le, Kaitlyn; Hartsough, Edward J et al. (2018) BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association. Cell Rep 25:1501-1510.e3|
|Teh, Jessica L F; Aplin, Andrew E (2018) Playing the Melanoma Endgame. Clin Cancer Res 24:4629-4630|
|Chua, Vivian; Lapadula, Dominic; Randolph, Clinita et al. (2017) Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma. Mol Cancer Res 15:501-506|
|Kageyama, Ken; Ohara, Masahiro; Saito, Kengo et al. (2017) Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis. J Transl Med 15:145|
|Behera, Reeti; Kaur, Amanpreet; Webster, Marie R et al. (2017) Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res 23:3181-3190|
|Cheng, Hanyin; Chua, Vivian; Liao, Connie et al. (2017) Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma. Mol Cancer Ther 16:516-528|
|Teh, Jessica L F; Purwin, Timothy J; Greenawalt, Evan J et al. (2016) An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma. Cancer Res 76:5455-66|
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