Translational Strategies for Repotrectinib in Neuroblastoma

Abstract

Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/ FAK, which have all been implicated in the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in combination with chemotherapy as a potential therapeutic approach for relapsed/refractory neuroblastoma.In vitro sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. In vivo antitumor effect of repotrectinib monotherapy, and in combination with chemotherapy, was evaluated using a genotypically diverse cohort of patient-derived xenograft (PDX) models of neuroblasto-ma. Repotrectinib had comparable cytotoxic activity across cell lines irrespective of ALK mutational status. Combination with chemotherapy demonstrated increased antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival compared with vehicle and ensartinib in PDX models (P < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in ALKmutant and ALK wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.

FYN: emerging biological roles and potential therapeutic targets in cancer

“…A significant antitumor effect is observed in non-small cell lung cancer patients treated with repotrectinib [ 178 ]. Repotrectinib showed significant antitumor effects in neuroblastoma models and was more effective when combined with chemotherapy [ 179 , 180 ].…”

Cucurbitacin IIa promotes the immunogenic cell death‑inducing effect of doxorubicin and modulates immune microenvironment in liver cancer

“…2A , CUIIa promoted DOX cytotoxicity in HepG2 cells. The combination index (CI) was used to evaluate the combined effect of DOX plus CUIIa ( 27 ), namely, synergistic (CI<1), additive (CI=1) or antagonistic (CI>1) effects ( 28 ). The IC 50 of DOX monotherapy was 1.1 μ M for HepG2 cells, while the IC 50 of CUIIa monotherapy was 31.5 μ M. When used in combination, the inhibition rate reached 50% in CUIIa (2.85 μ M) plus DOX (0.28 μ M) group (10:1 ratio), and meanwhile the calculated CI was equal to 0.36 ( Fig.…”

Anticancer activity features of imidazole-based ionic liquids and lysosomotropic detergents: in silico and in vitro studies

“…The interactions of these compounds with a Sirtuin-1 were predicted by docking analysis and further con rmed by a thermal shift assay. It should be noted that Sirtuin-1, Aurora A and JAK2 have been considered by a number of authors as a promising biotargets for anticancer therapy, including neuroblastoma and leukaemia types [33][34][35][36][37][38][39][40][41][42].…”