PT  - JOURNAL ARTICLE
AU  - Briseño-Díaz, Paola
AU  - Schnoor, Michael
AU  - Bello-Ramirez, Martiniano
AU  - Correa-Basurto, Jose
AU  - Rojo-Domínguez, Arturo
AU  - Arregui, Leticia
AU  - Vega, Libia
AU  - Núñez-González, Enrique
AU  - Palau-Hernández, Luis Andres
AU  - Parra-Torres, Carlos Guadalupe
AU  - García Córdova, Óscar Manuel
AU  - Zepeda-Castilla, Ernesto
AU  - Torices-Escalante, Eduardo
AU  - Domínguez-Camacho, Leticia
AU  - Xoconostle-Cazares, Beatriz
AU  - Meraz-Ríos, Marco Antonio
AU  - Delfín-Azuara, Sandra
AU  - Carrión-Estrada, Dayan Andrea
AU  - Villegas-Sepúlveda, Nicolas
AU  - Hernández-Rivas, Rosaura
AU  - Thompson-Bonilla, Maria del Rocio
AU  - Vargas, Miguel
TI  - Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer
AID  - 10.26508/lsa.202302019
DP  - 2023 Dec 01
TA  - Life Science Alliance
PG  - e202302019
VI  - 6
IP  - 12
4099  - https://www.life-science-alliance.org/content/6/12/e202302019.short
4100  - https://www.life-science-alliance.org/content/6/12/e202302019.full
SO  - Life Sci. Alliance2023 Dec 01; 6
AB  - 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.