Our long-term goal is to develop therapeutic strategies that improve the survival of patients with disseminated melanoma by potentiating new and existing targeted therapies. The clinical success of BRAF- and BRAF/MEK-targeted therapy suggests that high frequency disease control may one day be a reality for genetically defined sub- groups of patients with melanoma. Despite this progress, few advances have been made in developing targeted therapeutic strategies for the 15-20% of patients whose melanomas harbor activating NRAS mutations. Although significant progress has been made in the use of immunotherapy in melanoma patients, only half of those treated respond and many of these ultimately become resistant. In NRAS-mutant melanoma the MEK inhibitor binimetinib (MEK-162) is the first targeted agent to show efficacy in patients. This drug, while showing some clinical activity, is associated with modest response rates and a median progression-free survival (PFS) of ~3 months. Research by our group and others has suggested that this limited benefit may result from the escape of limited numbers of cells that ultimately repopulate the tumor. The reasons underlying this escape are likely to be complex and are thought to result from the inherent heterogeneity of melanoma. Together these data suggest the tumor to be composed of multiple cellular populations that show differential responses to drug. The study of clonality in melanoma and the characterization of the sub-populations of cells that evade therapy represent major technical challenges and remain largely unexplored. The overarching goal of this R21 application is to define the heterogeneity of response of NRAS-mutant melanomas to MEK inhibition and to develop combination therapy strategies that target these adaptations. We will use sophisticated single cell RNA and DNA analysis techniques to characterize the clonal heterogeneity of both NRAS-mutant melanoma cell lines and patient specimens at the single cell level and will investigate how MEK inhibition alters the clonal mix. We will perform bioinformatic analyses to identify the key pathways responsible for therapeutic escape at the single cell level and will test combination therapy strategies that abrogate these in vitro and in vivo with the goal of abrogating resistance. These studies will form the groundwork for future funding applications to develop clinically relevant drug combinations.
At this time, targeted therapy strategies are limited for the 15-20% of patients whose melanomas harbor NRAS mutations. Although there is evidence that MEK inhibitors have efficacy against NRAS-mutant melanoma, minor subpopulations of cells always escape therapy, leading to the acquisition of resistance. The aim of the application is to use single cell RNA and DNA analysis to model the clonal diversity of NRAS-mutant melanoma and to determine how MEK inhibition alters this. We will then use the single cell level mutation/expression data to develop combination therapy strategies that limit resistance to MEK inhibition allowing us to develop the proof-of-concept that will in future allow us to deliver durable responses to NRAS-mutant melanoma patients.
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| Phadke, Manali; Remsing Rix, Lily L; Smalley, Inna et al. (2018) Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Mol Oncol 12:74-88 |
| Faião-Flores, F; Alves-Fernandes, D K; Pennacchi, P C et al. (2017) Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene 36:1849-1861 |
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| Li, Jiannong; Smalley, Inna; Schell, Michael J et al. (2017) SinCHet: a MATLAB toolbox for single cell heterogeneity analysis in cancer. Bioinformatics 33:2951-2953 |
| Emmons, Michael F; Faião-Flores, Fernanda; Smalley, Keiran S M (2016) The role of phenotypic plasticity in the escape of cancer cells from targeted therapy. Biochem Pharmacol 122:1-9 |
| Smalley, Keiran S M; Eroglu, Zeynep; Sondak, Vernon K (2016) Combination Therapies for Melanoma: A New Standard of Care? Am J Clin Dermatol 17:99-105 |
| Smalley, Keiran S M; Fedorenko, Inna V; Kenchappa, Rajappa S et al. (2016) Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer 139:1195-201 |
| Sharma, Ritin; Fedorenko, Inna; Spence, Paige T et al. (2016) Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition. J Proteome Res 15:4476-4489 |
| Fedorenko, Inna V; Evernden, Brittany; Kenchappa, Rajappa S et al. (2016) A rare case of leptomeningeal carcinomatosis in a patient with uveal melanoma: case report and review of literature. Melanoma Res 26:481-6 |
