Valerie De Luca
Valerie De Luca
Valerie De Luca
Helios Scholar
School: Arizona State University
Hometown: Glendale, Arizona
Mentor: William Hendricks, Ph.D.
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BRAFV600E homozygosity as a potential indicator of increased response to treatment of cutaneous melanoma

Targeted BRAF and MEK inhibitors (BRAFi and MEKi) have revolutionized treatment for the 60% of cutaneous melanoma patients with the BRAFV600E mutation.  Despite improvements in survival conferred by these therapeutics, resistance can emerge within six months of treatment. This necessitates the identification of biomarkers that predict long-term response.  To this end, we performed a comprehensive genomic analysis of a clinical trial patient who experienced an extraordinarily prolonged response on the MEKi E6201 (>70 cycles of treatment). Notably, the patient harbored a homozygous BRAFV600E mutation, which is seen in only ~20% of BRAFV600E patients and has recently been associated with increased sensitivity to the BRAFi vemurafenib in preclinical and retrospective clinical reports. This increased sensitivity is hypothesized to be caused by the lack of wildtype BRAF, and thus evasion of signaling reactivation through wild-type BRAF dimerization with the vemurafenib-mutant BRAF complex. Given the patient’s genomic context, we aimed to test whether BRAFV600E homozygosity also correlates with increased sensitivity to inhibitors of downstream MAPK components, specifically MEKi. We performed drug dose response assays on three homozygous and two heterozygous BRAFV600E melanoma cell lines for E6201, cobimetinib (MEKi), trametinib (Meki), and vemurafenib. Potency (IC50) across drugs was used to determine whether there was differential sensitivity between the homo- and heterozygotes. Preliminary data suggests that zygosity alone does not predict sensitivity to MEKi, and that E6201 is less potent than other MEKi. However, ongoing work includes analysis of downstream signaling post-treatment, as well as the inclusion of additional cell lines to avoid rejecting the hypothesis due to small sample size.  Future directions include the use of isogenic cell lines to eliminate the complex and varied genotypes seen in our current lines, in addition to the testing of alternative hypotheses that may explain the patient’s prolonged response (such as mechanisms that deter acquired resistance).