Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer

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 treatmen...

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Published in:Life science alliance 2023-12, Vol.6 (12), p.e202302019
Main Authors: Briseño-Díaz, Paola, Schnoor, Michael, Bello-Ramirez, Martiniano, Correa-Basurto, Jose, Rojo-Domínguez, Arturo, Arregui, Leticia, Vega, Libia, Núñez-González, Enrique, Palau-Hernández, Luis Andres, Parra-Torres, Carlos Guadalupe, García Córdova, Oscar Manuel, Zepeda-Castilla, Ernesto, Torices-Escalante, Eduardo, Domínguez-Camacho, Leticia, Xoconostle-Cazares, Beatriz, Meraz-Ríos, Marco Antonio, Delfín-Azuara, Sandra, Carrión-Estrada, Dayan Andrea, Villegas-Sepúlveda, Nicolas, Hernández-Rivas, Rosaura, Thompson-Bonilla, Maria Del Rocio, Vargas, Miguel
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Humans
Mice
Pancreatic Neoplasms
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
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Summary: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.
ISSN:2575-1077
2575-1077
DOI:10.26508/lsa.202302019