Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.
Paola Briseño-DíazMichael SchnoorMartiniano Bello-RamirezJose Correa-BasurtoArturo Rojo-DomínguezLeticia ArreguiLibia Vega-LoyoEnrique Núñez-GonzálezLuis Andres Palau-HernándezCarlos Guadalupe Parra-TorresOscar Manuel García CórdovaErnesto Zepeda-CastillaEduardo Torices-EscalanteLeticia Domínguez-CamachoBeatriz Xoconostle-CazaresMarco Antonio Meraz-RiosSandra Delfín-AzuaraDayan Andrea Carrión-EstradaNicolas Villegas-SepulvedaRosaura Hernández-RivasMaria Del Rocio Thompson-BonillaMiguel VargasPublished in: Life science alliance (2023)
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.