672 Targeting lncRNAs AC and BX reveals their critical role in melanoma and allows to identify novel phosphor-catalytic vulnerabilities

Abstract

More than 80% percent of melanomas harbor mutations in either NRAS or BRAF. Our goal was to identify targets that are key in the process of melanocyte tumorigenesis and molecules that can be used to prevent this event. We have identified two long non-coding RNA (lncRNA) transcripts AC and BX key in the process of melanocyte tumorigenesis and melanoma progression. Tested in a variety of BRAF and NRAS mutated, drug resistant melanoma cell lines and other NRAS cancers such as lung ca and neuroblastoma, RNAi and antisense oligonucleotide (ASO) mediated knockdown of AC and BX lead to a vast reduction of tumor growth in vivo. High-throughput Kinase Activity Mapping (HT-KAM), a method for mapping phospho-catalytic dependencies of cells, unveiled AC and BX dependent kinases. Their inhibition not only mimic the knockdown-effects but also shows synergistic effect with ASO treatment. In addition, by using HT KAM technology, we were able to identify phospho-catalytic vulnerabilities of melanoma cells resistant to current targeted therapeutics. Moreover, knockdown of our transcripts causes a significant induction of PDL1 receptor ligand (key for immunotherapy response). Our studies are innovative because we offer new therapeutics and a diagnostic test to identify new drug combinations to restore therapeutic response for immune and targeted therapy.