RS cells show expression and activation of components of the PI3K-AKT axis that can be targeted by duvelisib, which leads to activation of GSK3β and results in MCL1 and MYC ubiquitination and degradation via the proteasome. Downregulation of MCL1 and MYC sensitizes RS cells to venetoclax-mediated intrinsic apoptosis. GPCR, G-protein–coupled receptor; p, phosphorylation; ub, ubiquitination; UPS, ubiquitin proteasome system. Figure designed by Matteo Oliverio. The figure has been adapted from Iannello et al that begins on page 3378.