Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers collateral sensitivity to ALK inhibitors in high-risk neuroblastoma

Abstract

Abstract Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma (NB), but resistance to ALK inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing NB; inhibition of miR-1304-5p decreased, while mimics increased the sensitivity of NB cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in NB, inducing apoptosis both in vitro and in vivo. In particular, on combined treatment of NB patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth was observed although tumours rapidly regrew on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk NB although prolonged therapy is likely required to prevent relapse, rendering high-risk NB a chronic rather than a lethal disease.