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

Sep 24, 2026

Uploaded by Margaret

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, driven by rising incidence and poor survival, with most patients carrying KRAS mutations, especially KRASG12D and KRASG12V. KRAS controls PDAC development, growth, epigenetically dysregulated differentiation, and survival through downstream MAPK-ERK and PI3K-AKT/mTOR signaling. KRAS-dependent tumor initiation involves acinar-to-ductal metaplasia and PanIN, shaping an immunosuppressive TME. Despite KRAS-signaling inhibitors, PDAC cells escape via compensatory mechanisms such as MEK/ERK pathway activation and YAP1 upregulation.

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CategoryHealthcare

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1. Introduction

Review KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy Enrico Gurreri 1,2, Giannicola Genovese 2,3,4,5, Luigi Perelli 2, Antonio Agostini 1, Geny Piro 1, Carmine Carbone 1,* and Giampaolo Tortora 1,6 Citation: Gurreri, E.; Genovese, G.; Perelli, L.; Agostini, A.; Piro, G.; Carbone, C.; Tortora, G. KRASDependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy. Int. J. Mol. Sci. 2023, 24, 9313. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24119313 Academic Editor: Laura Paleari Received: 5 May 2023 Revised: 18 May 2023 Accepted: 24 May 2023 Published: 26 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; [enrico.gurreri01@icatt.it](enrico.gurreri01@icatt.it) (E.G.); [antonio.agostini@unicatt.it](antonio.agostini@unicatt.it) (A.A.); [geny.piro@policlinicogemelli.it](geny.piro@policlinicogemelli.it) (G.P.); [giampaolo.tortora@policlinicogemelli.it](giampaolo.tortora@policlinicogemelli.it) (G.T.) 2 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA; [ggenovese@mdanderson.org](ggenovese@mdanderson.org) (G.G.); [lperelli@mdanderson.org](lperelli@mdanderson.org) (L.P.) 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA 4 David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA 5 Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA 6 Medical Oncology, Universit Cattolica del Sacro Cuore, 00168 Rome, Italy * Correspondence: [carmine.carbone@policlinicogemelli.it](carmine.carbone@policlinicogemelli.it) 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-AKTmammalian 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 PDACand analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms. Keywords: pancreatic cancer; KRAS; KRAS inhibitors; KRAS-dependency; resistance; escaping 1. Introduction Pancreatic ductal adenocarcinoma (PDAC) is still

FAQs

Why is pancreatic ductal adenocarcinoma (PDAC) considered highly lethal?

PDAC has increasing incidence and very poor overall survival, with less than 5% five-year survival reported in the text. It is frequently diagnosed at advanced stages (locally advanced or metastatic).

What roles does KRAS play in PDAC development and progression?

In KRAS-mutated PDAC, KRAS regulates development, cell growth, epigenetic differentiation, and survival. It activates key downstream pathways including MAPK-ERK and PI3K-AKT/mTOR signaling and promotes acinar-to-ductal metaplasia and PanIN formation.

How do PDAC cells escape resistance to KRAS inhibitors?

The review describes compensatory escape mechanisms that counteract KRAS inhibitor efficacy. Examples include activation of MEK/ERK signaling and upregulation of YAP1.

Sep 24, 2026

Uploaded by Margaret