KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance - Review

Sep 21, 2026

KRAS is a small GTPase that is among the most frequently mutated oncogenes in human cancer. The article reviews KRAS biology and therapeutic strategies aimed at inhibiting oncogenic KRAS, including mutation-specific small molecules, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and immunostimulatory approaches. It emphasizes resistance as a major barrier, describing direct mechanisms such as KRAS mutation-driven drug insensitivity and copy-number changes, as well as indirect and non-mutational resistance involving pathway reactivation, epigenetic and transcriptional remodeling, and tumor microenvironment alterations.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages23

Reading Time58 min

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Introduction

KRAS Structure and Function

KRAS Activity Is Regulated at Multiple Levels

Review KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance Leonard J. Ash 1,2, Ottavia Busia-Bourdain 1, Daniel Okpattah 3, Avrosina Kamel 1,4, Ariel Liberchuk 1,4 and Andrew L. Wolfe 1,2,3,5, * Citation: Ash, L.J.; Busia-Bourdain, O.; Okpattah, D.; Kamel, A.; Liberchuk, A.; Wolfe, A.L. KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Curr. Oncol. 2024, 31, 2024–2046. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/curroncol31040150](10.3390/curroncol31040150) Received: 13 March 2024 Revised: 29 March 2024 Accepted: 1 April 2024 Published: 3 April 2024 Copyright: © 2024 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 Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA 2 Molecular, Cellular, and Developmental Biology Subprogram of the Biology Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA 3 Biochemistry Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA 4 Macaulay Honors College, Hunter College, City University of New York, New York, NY 10065, USA 5 Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA * Correspondence: [awolfe@genectr.hunter.cuny.edu](awolfe@genectr.hunter.cuny.edu) Abstract: KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations. Keywords: KRAS; cancer; immunotherapy; targeted therapy; resistance; oncogene; inhibitors; mutation 1. Introduction 1.1. KRAS Structure and Function KRAS is a small GTPase that ranks among the most commonly mutated oncogenicdrivers in cancer. KRAS mutations are implicated in 25–30% of all human cancers, about 19% of non-small cell lung cancers (NSCLCs), about 40% of colorectal cancers (CRCs), and about 73% of pancreatic ductal adenocarcinoma (PDAC) cases (Figure 1) [1,2] . KRASis a member of the RAS family of evolutionarily related genes, which also includes the commonly mutated HRAS and NRAS. The same genomic locus encodes for two alternatively spliced proteins, KRAS4A and KRAS4B, which are identical except for the final C-terminal hypervariable exon. RAS proteins are GTPase molecular switches that cycle between inactive, GDP-bound forms and active GTP-bound forms. The active forms bind to downstream effectors to stimulate their activity. KRAS is composed of two major structural regions: (1) the G-domain and (2) the C-terminal unstructured hypervariable region. The G-domain (

FAQs

Which therapeutic approaches are discussed for inhibiting oncogenic KRAS?

The article covers several strategies, including small molecules targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory approaches.

What are the main categories of KRAS inhibitor resistance described?

Resistance mechanisms are grouped into direct resistance (e.g., KRAS mutations reducing efficacy or copy-number alterations increasing mutant KRAS expression), indirect resistance (e.g., mutations that rescue mutant KRAS-dependent cells by reactivating the same or alternative pathways), and non-mutational resistance (e.g., epigenetic marks, transcriptional reprogramming, and tumor microenvironment changes).

How is KRAS activity regulated after the protein is synthesized?

KRAS activity is regulated through post-translational lipid modifications to its C-terminal hypervariable region, including prenylation by FTase or GGTase and subsequent modifications by RCE1 and ICMT, with palmitoylation further promoting membrane localization.

Sep 21, 2026

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