Abstract C157: Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib

Abstract

Abstract Our study investigates the efficacy of targeted therapies for Esophageal Adenocarcinoma (EAC) tumors harboring an activating PIK3CA mutation and inactivating CDKN2A mutation. We tested the small molecule inhibitors alpelisib, which targets the Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit (PIK3CA), and palbociclib, which targets Cyclin D kinase 4/6 (CDK4/6), in EAC in vitro organoid and in vivo mouse models. EAC and Gastric cancer (GC) organoid models were treated with single agent alpelisib or palbociclib on a log scale to determine their IC50 values. An EAC organoid harboring activating PIK3CA E545K and inactivating CDKN2A D74A mutations demonstrated more significant growth inhibition when treated with each agent alone versus standard of care chemotherapy. Subsequent experiments involved combination treatment of our EAC-mutant organoid with alpelisib and palbociclib as well as a representative GC organoid and EAC organoids lacking these specific mutations as controls. We confirmed PIK3CA downstream target engagement after alpelisib treatment by qPCR, western blot analysis and immunofluorescence analysis. Once in vitro efficacy was confirmed, EAC-mutant organoids were transplanted into mice by either subcutaneous or orthotopic injections and treated with chemotherapy, alpelisib and palbociclib alone or in combination. Our data demonstrate that a PIK3CA/CDKN2A mutated patient-derived EAC organoid is sensitive to alpelisib and palbociclib in a dose dependent manner, and analysis of PIK3CA downstream targets by western and qPCR was consistent with growth inhibition of treated organoids. These findings offer support for the use of alpelisib and palbociclib in the treatment of EAC patients with PIK3CA/CDKN2A mutations. Citation Format: Naryan Rustgi, Thomas Ryan, Jin Cho, Ryan Moy, Sam Yoon, Sandra Ryeom, Changhwan Yoon. Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C157.