Abstract 1001: Treatment of RB1-intact cancers with CDK4/6 inhibitor combination therapy

Abstract

Abstract Synthetic CDK4/6 inhibitors exert anti-tumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis and increased immunogenicity. These agents currently have an indication in advanced breast cancers, and are in clinical trials for many other solid tumors. Hepatocellular carcinoma (HCC) is one of promising targets of CDK4/6 inhibitors. RB family function is often aberrated in the initiation of HCC, however, this is revivable as RB family genes are rarely mutated or deleted in this malignancy. Loss of all Rb family members in Trp53-/- mouse liver resulted in hepatoma reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into HepG2 cells induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an IKKβ inhibitor. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with KKβ inhibitor was significantly more effective in HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact K-Ras mutated lung and colon cancers. These findings provide proof of principle for the treatment of a wide variety of RB1-intact cancers using CDK4/6 inhibitors in combination with an appropriate kinase inhibitor. In this presentation, we will propose a new therapeutic approach to RB1-intact solid tumors. Citation Format: Chiaki Takahashi. Treatment of RB1-intact cancers with CDK4/6 inhibitor combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1001.