Targeting Rheostatic Mechanisms in Melanoma

Providence Health & Services - Oregon, Renton WA

Investigators

Linked publications & trials

Abstract

Abstract Cutaneous melanoma is highly lethal and the fifth most common cancer in the U.S. Peak incidence is in middle age adults but the elderly, young adults and even children are affected. Among all cancer types, melanoma is one of the most aggressive in its propensity for extremely early metastasis. Metastatic melanoma is difficult to eradicate, and treatment resistance is a common problem among patients receiving systemic therapy. Genetic causes of melanoma align along a continuum of RAS protein signaling whereby BRAFV600E mutation is the most common driver. The mutant BRAFV600E protein depends on MAPK signaling for both initiation and maintenance of tumor growth. Targeting this abnormally-activated pathway with RAF and MEK inhibitors have had limited success in treating this disease due to MAPK signaling reactivation, causing drug resistance. Thus, more mechanistic insights are needed in order to develop combination therapies that can circumvent resistance. We reported that aberrant activation of the small GTPase ARF6, a protein that controls intracellular trafficking, accelerates metastasis of BRAFV600E melanoma. Prior to metastasis, ARF6 is also required for efficient tumor development and growth in mice with BRAFV600E melanoma. Combined, these data position ARF6 as a key regulator at multiple points in disease progression. Our preliminary data suggest a novel role for ARF6 in MAPK signaling by regulating the amount of mutant BRAF protein. Activation of ARF6 leads to increased BRAFV600E protein and MAPK signaling while inhibition of ARF6 decreases BRAFV600E protein. We have found that ARF6 can be activated in response the pharmacologic inhibition of BRAFV600E and that active ARF6 can potentiate a rebound/recovery in MAPK signaling after targeted therapy, protecting against apoptosis induced by BRAFV600E inhibition. Importantly, our preliminary findings suggest that inhibition of ARF6 can sensitize melanoma to MAPK targeted therapy, including tumors that are resistant to combination RAF + MEK inhibitors. Using genetic and pharmacologic approaches, our goals are to dissect the role(s) of ARF6 in BRAF protein expression, discover new role(s) for ARF6 in tumor cell function, and test the efficacy of ARF6 inhibitors in restricting tumor progression. Pursuant to these goals, we will: 1) Determine if ARF6 control BRAFV600E protein expression or stability; 2) Test the hypothesis that ARF6 fortifies melanoma survival and resistance to MAPK targeted therapy; 3) Test if inhibition of ARF6 sensitizes MAPK-inhibitor resistant BRAFV600E patient-derived xenografts (MPDX) to RAF+MEK combination therapy. Successful completion of the aims in this proposal will identify new mechanisms of targeted therapy resistance that may be amenable to therapeutic intervention and may position ARF6 as a potential therapeutic target in RAS-mutant cancers.