Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence.

• Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFβ, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.