Lestaurtinib inhibits therapy resistant ovarian cancer

Ovarian cancer is the deadliest gynecological cancer, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need to devise novel therapeutic strategies. Through an unbiased drug screen, we identified lestaurtinib as a potent inhibitor of chemotherapy- and poly-ADP ribose polymerase inhibitors (PARPi)-sensitive and -resistant ovarian cancer cells and patient-derived xenografts (PDXs). RNA-sequencing revealed that lestuartinib potently suppressed JAK/STAT signaling. Lestaurtinib efficacy was directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive activation of this pathway and genetic ablation of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib displayed synergy with cisplatin and olaparib, including in a model of PARPi resistance. Interestingly, the most well-known JAK/STAT inhibitor, ruxolitinib, completely failed to inhibit any cell line or PDX model tested. This drug-specific discrepancy was related to STAT phosphorylation profiles where lestaurtinib was shown to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3 whereas ruxolitinib failed to block S727. Mechanistically, lestaurtinib additionally inhibited JNK and ERK activity, leading to broad suppression of STAT phosphorylation. However, combining ruxolitinib with a JNK or ERK inhibitor was synergistic at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, or other monotherapy or combinatorial strategies that converge on JAK/STAT signaling, is worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. MDAH and OVSAHO (OVS) cells treated with DMSO vehicle (Veh) or 500nM lestaurtinib (Lest) in triplicate for 24 hours and conducted gene expression profiling via RNAseq to understand what genes are regulated by lestaurtinib treatment.