Mutations to a gene known as BRAF (i.e. BRAFV600E) are present in more than half of papillary thyroid carcinomas (PTCs) and nearly 75 percent of melanomas. Selective inhibitors that target the BRAFV600E oncoprotein, such as vemurafenib, have shown promise as a treatment for aggressive PTC in clinical trials. However, most patients eventually develop resistance to the therapy and the disease progresses. Beth Israel Deaconess Medical Center researchers led by Carmelo Nucera, MD, PhD, Assistant Professor at Harvard Medical School and Associate at the Thyroid Cancer Translational Research Laboratory of the BROAD Institute of MIT and Harvard, investigated the mechanisms of primary and secondary treatment resistance in patient-derived invasive PTC cells. 

Cancer is an evolutionary system and based on cytogenetically diverse clones. Driven by various selective pressures including anti-cancer therapy, tumor heterogeneity may be the fundamental element allowing tumors to expand resistant clones. Understanding the cytogenetic heterogeneity and genomic alterations of thyroid carcinoma that emerge during therapy with BRAFV600E inhibitors is crucial to improving clinical studies and will help delineate mechanisms of tumor progression.

When the team characterized a sub-population of human thyroid tumor cells with primary resistance, they found that the resistant tumor cells showed specific abnormalities in genes and genetic pathways associated with cell cycle checkpoint control, DNA damage-response, and chromosome stability. Treating these resistant cells with combined therapy (vemurafenib plus palbociclib) successfully induced tumor cell death in the cells harboring these resistance-conferring mutations.

The findings suggest for the first time that targeting these specific abnormalities represents a novel therapeutic strategy to treat resistant BRAFV600E-positive PTC. Moreover, the research suggests that combined therapy could target tumor cells either with primary or secondary resistance to first line medication, thereby keeping this population of aggressive BRAFV600E-positive PTC cells in check. The findings were reported in the journal Oncotarget and presented by Dr. Nucera at the 2018 Annual ITOG Meeting.