Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.

Gurreri, E., Genovese, G., Perelli, L., Agostini, A., Piro, G., Carbone, C., Tortora, G., KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy, <<INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES>>, 2023; 24 (11): N/A-N/A. [doi:10.3390/ijms24119313] [https://hdl.handle.net/10807/271584]

KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy

Gurreri, Enrico;Genovese, Giannicola;Perelli, Luigi;Agostini, Antonio;Carbone, Carmine;Tortora, Giampaolo
2023

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.
2023
Inglese
Gurreri, E., Genovese, G., Perelli, L., Agostini, A., Piro, G., Carbone, C., Tortora, G., KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy, <<INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES>>, 2023; 24 (11): N/A-N/A. [doi:10.3390/ijms24119313] [https://hdl.handle.net/10807/271584]
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