Thursday, June 21, 2018

Another possible option for NRAS mutant melanoma patients

Sadly, today's post is in keeping with those of the past two days, in that this abstract doesn't give a great deal of definitive info.  By way of explanation, here is a link to prior posts (with links within) that address treatment for folks with:  NRAS-mutant melanoma

This ASCO 2017 report noted:  NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.

After which I wrote this:  In this study, 224 NRAS mutated melanoma patients were studied. 180 were treated with ipi, 98 with anti-PD-1 and 1 was given the ipi/nivo combo.  The overall response rate was 15% for those treated with ipi and 34% for those treated with anti-Pd-1....which is in keeping with response rates for those drugs generally.

Despite the fairly optimistic (For melanoma world, don't 'cha know???!!) report above, there are other studies (and more importantly ~ real live NRAS friends and peeps) who have struggled with attaining good responses on current therapies.  The mice and researchers now share this:

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma. Echevarria-Vargas, Reyes-Uribe, Guterres, et al. EMBO Mol Med. 2018 Apr 12. 

Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.

Perhaps this will help send therapy for NRAS-mutant melanoma in a better direction.  Hang tough my dear NRAS ratties!!! - c

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