Reverse molecular pharmacology identifies the non-canonical axis of IRAK as a chemoresistance factor in neuroblastoma
Le Grand, M.; Buxbaum, C.; Kerherve, M.; Gaucher, F.; Martinez-Rubio, A.; Taha, M.; Muller, K.; Mouysset, B.; Bomane, A.; Letard, S.; Failes, T. W.; Arndt, G. M.; Chebbi, S.; Labaronne, E.; Cavalli, F. M. G.; ANDRE, N.; Broutier, L.; Shaked, Y.; Pasquier, E.
Show abstract
Owing to chemoresistance, the prognosis of relapsed neuroblastoma is dismal with less than 10% of patients surviving after 5 years. We developed a reverse molecular pharmacology approach that is based on high-throughput drug screening coupled with chemo-informatic and transcriptomic analyses. This led to the identification of IRAK1 as a key chemoresistance factor in neuroblastoma. By performing functional and pharmacological drug combination screens targeting IRAK1, we revealed a synergy between IRAK1 inhibition/silencing and BET, EGFR and mTOR inhibitors as well as microtubule-targeting agents. The synergistic combination of microtubule-targeting agent, vincristine and IRAK inhibitors was then confirmed in tumor spheroids, patient-derived tumoroids and a syngeneic orthotopic mouse model. Mechanistically, IRAK inhibition potentiated the pro-apoptotic and cell cycle arrest properties of vincristine via a pathway involving the PIDDosome complex rather than its canonical MyDDosome axis. Altogether, this study represents a proof-of-concept of our reverse molecular pharmacology approach to quickly develop biology-guided drug combinations, that could be applied to any other human diseases.
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