Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt

Noritaka Tanaka; Hiromichi Ebi

doi:10.1111/cas.16441

journal article Open Access Dec 27, 2024

Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt

Noritaka Tanaka Hiromichi Ebi

Cancer Science Vol. 116 No. 3 pp. 600-612 · Wiley

View at Publisher Save 10.1111/cas.16441

Abstract

ABSTRACTKRAS was long deemed undruggable until the discovery of the switch‐II pocket facilitated the development of specific KRAS inhibitors. Despite their introduction into clinical practice, resistance mechanisms can limit their effectiveness. Initially, tumors rely on mutant KRAS, but as they progress, they may shift to alternative pathways, resulting in intrinsic resistance. This resistance can stem from mechanisms like epithelial‐to‐mesenchymal transition (EMT), YAP activation, or KEAP1 mutations. KRAS inhibition often triggers cellular rewiring to counteract therapeutic pressure. For instance, feedback reactivation of signaling pathways such as MAPK, mediated by receptor tyrosine kinases, supports tumor cell survival. Inhibiting KRAS disrupts protein homeostasis, but reactivation of MAPK or AKT can restore it, aiding tumor cell survival. KRAS inhibition also causes metabolic reprogramming and protein re‐localization. The re‐localization of E‐cadherin and Scribble from the membrane to the cytosol causes YAP to translocate to the nucleus, where it drives MRAS transcription, leading to MAPK reactivation. Emerging evidence indicates that changes in cell identity, such as mucinous differentiation, shifts from alveolar type 2 to type 1 cells, or lineage switching from adenocarcinoma to squamous cell carcinoma, also contribute to resistance. In addition to these nongenetic mechanisms, secondary mutations in KRAS or alterations in upstream/downstream signaling proteins can cause acquired resistance. Secondary mutations in the switch‐II pocket disrupt drug binding, and known oncogenic mutations affect drug efficacy. Overcoming these resistance mechanisms involves enhancing the efficacy of drugs targeting mutant KRAS, developing broad‐spectrum inhibitors, combining therapies targeting multiple pathways, and integrating immune checkpoint inhibitors.

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References

65

[1]

10.1158/2159‐8290.cd‐21‐1494

[2]

10.1158/1541‐7786.mcr‐15‐0203

[3]

10.1074/jbc.ra119.008653

[4]

10.1093/jnci/djr523

[5]

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Jonathan M. Ostrem, Ulf Peters, Martin L. Sos et al.

Nature 10.1038/nature12796

[6]

10.1038/s41591‐022‐02007‐7

[7]

10.1021/acs.jmedchem.1c01688

[8]

10.1158/2159‐8290.cd‐23‐1138

[9]

10.1038/s41589‐024‐01565‐w

[10]

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

Christopher J. Schulze, Kyle J. Seamon, Yulei Zhao et al.

Science 10.1126/science.adg9652

[11]

10.1038/s41586‐024‐07205‐6

[12]

10.1038/s41586‐023‐06123‐3

[13]

A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell Survival

Anurag Singh, Patricia Greninger, Daniel Rhodes et al.

Cancer Cell 10.1016/j.ccr.2009.03.022

[14]

10.1016/j.cell.2014.06.004

[15]

10.1016/j.cell.2014.06.003

[16]

10.1038/s43018‐021‐00184‐x

[17]

10.1016/j.celrep.2018.01.051

[18]

10.1016/j.molcel.2009.08.002

[19]

10.1158/1078‐0432.ccr‐20‐2077

[20]

10.1158/2159‐8290.cd‐19‐1167

[21]

10.1158/2159‐8290.cd‐22‐1420

[22]

10.1056/nejmoa2103695

[23]

Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany

Jan A. Stratmann, Friederike C. Althoff, Paula Doebel et al.

European Journal of Cancer 10.1016/j.ejca.2024.113911

[24]

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

Xinyuan Tong, Ayushi S. Patel, Eejung Kim et al.

Cancer Cell 10.1016/j.ccell.2024.01.012

[25]

Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer

Martin C. Whittle, Kazuhiro Nakamura, Amy N. Abell et al.

Cell 10.1016/j.cell.2012.02.053

[26]

10.1158/2159‐8290.cd‐15‐1377

[27]

10.1158/1078‐0432.ccr‐19‐3523

[28]

10.1038/s41586‐019‐1884‐x

[29]

10.1126/science.abn4180

[30]

10.1101/2024.05.19.594824

[31]

10.1016/j.celrep.2020.03.021

[32]

10.1038/s43018‐023‐00575‐2

[33]

10.1038/s41586‐021‐04065‐2

[34]

Acquired Resistance to KRAS G12C Inhibition in Cancer

Mark M. Awad, Shengwu Liu, Igor I. Rybkin et al.

New England Journal of Medicine 10.1056/nejmoa2105281

[35]

10.1158/2159‐8290.cd‐21‐0365

[36]

10.1038/s41571‐020‐0340‐z

[37]

10.1172/jci155523

[38]

10.1038/ncomms14922

[39]

10.1158/2159‐8290.cd‐23‐0289

[40]

10.1158/2159‐8290.cd‐24‐0421

[41]

10.1016/j.molcel.2013.02.018

[42]

10.1016/j.devcel.2018.02.024

[43]

Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution

Dian Yang, Matthew G. Jones, Santiago Naranjo et al.

Cell 10.1016/j.cell.2022.04.015

[44]

Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor

William J. Zacharias, David B. Frank, Jarod A. Zepp et al.

Nature 10.1038/nature25786

[45]

10.1016/j.ccell.2020.06.012

[46]

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing

Ashley Maynard, Caroline E. McCoach, Julia K. Rotow et al.

Cell 10.1016/j.cell.2020.07.017

[47]

10.1186/s13045‐021‐01186‐z

[48]

10.1158/2159‐8290.cd‐24‐0740

[49]

10.1200/jco.2024.42.16_suppl.3007

[50]

10.1038/s42003‐021‐02149‐3

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Details

Published: Dec 27, 2024
Vol/Issue: 116(3)
Pages: 600-612
License: View

Authors

N

Noritaka Tanaka

Division of Molecular Therapeutics Aichi Cancer Center Research Institute Nagoya Japan

H

Hiromichi Ebi

Division of Molecular Therapeutics Aichi Cancer Center Research Institute Nagoya Japan; Division of Advanced Cancer Therapeutics Nagoya University Graduate School of Medicine Nagoya Aichi Japan

Funding

Japan Society for the Promotion of Science Award: 22K19473

Takeda Science Foundation

Princess Takamatsu Cancer Research Fund Award: 21‐25306

Cite This Article

Noritaka Tanaka, Hiromichi Ebi (2024). Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt. Cancer Science, 116(3), 600-612. https://doi.org/10.1111/cas.16441

Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt

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