DDDR-15. RESISTANCE TO TARGETED ANTI-MITOTICS IN GLIOBLASTOMA IS DRIVEN BY STAT3 ACTIVATION AND THERAPY INDUCED SENESCENCE

Abstract

Abstract Tumor cells require the mitotic spindle to drive chromosome separation in metaphase, which has made the spindle a compelling target for development of anti-mitotics. However, most of these spindle inhibitors target microtubules and can thereby be highly neurotoxic. This has motivated development of targeted anti-mitotics that inhibit non-microtubule components of the spindle, including kinesins and mitotic kinases. These drugs are not neurotoxic and prolong survival in tumor patients, but resistance limits their efficacy. We reported (Kenchappa et al., Cell Reports, 2022) that resistance to one of these—ispinesib, a highly specific inhibitor of the mitotic kinesin Kif11—requires two functions of STAT3: activation of transcription in the nucleus and of oxidative phosphorylation in the mitochondria. Inhibiting both functions reverses ispinesib resistance. Furthermore, combining ispinesib with a CNS-permeant STAT3 inhibitor significantly prolongs survival over ispinesib alone in both immunocompetent and PDX GBM models. We now report that resistance to two other targeted anti-mitotics—alisertib (Aurora Kinase inhibitor) and volasertib (Polo Like Kinase inhibitor)—works similarly and can likewise be reversed with STAT3 inhibitors. For all three of these anti-mitotics, resistance goes hand-in-hand with development of therapy-induced senescence (TIS) in approximately half of GBM cells. TIS cells secrete a variety of soluble factors, referred to as the senescence associated secretory phenotype (SASP), which stimulate stemness, angiogenesis, and immunosuppression. We propose that: 1) TIS cells require STAT3 for survival, and that they in turn maintain a drug resistant state by suppressing mitosis in the remaining, non senescent cells through components of the SASP; and 2) by killing TIS cells, STAT3 inhibitors restore anti-mitotic sensitivity in the remaining, non-senescent tumor cells. We propose that this STAT3/TIS model of resistance may also apply to how resistance develops to other GBM therapies, and may guide similar translational approaches to enhancing therapeutic efficacy.