Synergy of a CDK4/6 inhibitor and an HDAC inhibitor in pancreatic cancer overcomes autophagy

Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant aggressive tumor with a poor prognosis and survival rate. Therapy resistance in PDAC is common and is attributed to metabolic plasticity, dense desmoplastic stroma, tumor heterogeneity, and immune evasion. Our previous study demonstrated synergy and efficacy of Panobinostat (Pan), a pan-HDAC inhibitor, and Abemaciclib (Abe), a CDK4/6 inhibitor, in PDAC cells. We aimed to identify the mechanism of these synergy effects as they can help in therapy efficacy and in overcoming resistance. Our mechanistic studies to understand the combination effects of Pan-Abe utilized transcriptomics and metabolomics experiments followed by Seahorse analysis. Abe treatment resulted in mitochondrial dysfunction whereas Pan treatment induced autophagy and lysosomal processes. We followed these studies using cell biological experiments assessing autophagy profile using fluorescence microscopy and western blotting. The Pan-Abe combination demonstrated metabolic dysfunction but did not induce robust autophagy response. Interestingly, the synergy of Pan-Abe from PDAC cells was confirmed in MIA PaCa-2 tumor xenograft model. Further studies are needed to understand the role of autophagic processes in the efficacy of Pan-Abe in PDAC.