Circumventing cancer drug resistance in the era of personalized medicine

Garraway, Levi A.; Jänne, Pasi A.

doi:10.1158/2159-8290.cd-12-0012

Cited by 503Drug Transport and Resistance MechanismsLung Cancer Treatments and MutationsCancer Cells and Metastasis

Circumventing cancer drug resistance in the era of personalized medicine

Garraway, Levi A., Jänne, Pasi A.·2012·Cancer Discovery

DOI 10.1158/2159-8290.cd-12-0012

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Abstract

All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance. Experimental approaches that can help predict the eventual clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, are rapidly identifying novel resistance mechanisms. In this review, we provide a historical background on drug resistance and a framework for understanding the common ways by which cancers develop resistance to targeted therapies. We further discuss advantages and disadvantages of experimental strategies that can be used to identify drug resistance mechanism(s). Significance: Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer. We provide a summary of current knowledge on drug resistance mechanisms and experimental strategies to identify and study additional drug resistance pathways. Cancer Discovery; 2(3); 214–26. ©2012 AACR.

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The majority of patients who respond well to initial targeted cancer therapy develop resistance.
“This is not surprising, since decades of research on targeted cancer therapy have shown that the majority of patients who respond well to initial treatment develop resistance.57, 58, 59, 60”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [58]
Low dependency on K-Ras signaling could confer intrinsic resistance to K-RasG12C inhibitors.
“Mechanistically, low dependency on K-Ras signaling could confer intrinsic resistance to K-RasG12C inhibitors.12,58,61”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [58]
Genomic heterogeneity arising from co-occurring mutations may contribute to the heterogeneous extent of adaptive resistance across KRAS mutant cancers.
“Genomic heterogeneity arising from a variety of co-occurring mutations may contribute to the heterogeneous extent of adaptive resistance across KRAS mutant cancers.57,58”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [58]
Most cancer therapeutics lack known markers for susceptibility or resistance.
“Although population-based studies have been successful in some instances (e.g., in lung cancers with mutations of EGFR or rearrangements involving ALK), the vast majority of cancer therapeutics have no known markers for susceptibility or resistance3.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [3]

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Authors: Garraway, L. A., & Jänne, P. A.
Affiliations: Brigham and Women's Hospital (US)
Authors' Affiliations: 1Department of Medical Oncology, 2Center for Cancer Genome Discovery, 3Lowe Center for Thoracic Oncology, and 4Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston; 5Department of Medicine, Brigham and Women's Hospital, Boston; and 6Broad Institute of Harvard and MIT, Cambridge, Massachusetts
ORCID: Garraway, Levi A.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2012-03-01
Volume: 2
Issue: 3
Pages: 214-226
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-12-0012
OpenAlex: W2103980474
Cited by: 503
References: 93
Citations by year: 2026: 20 · 2025: 22 · 2024: 26 · 2023: 34 · 2022: 29 · 2021: 35 · 2020: 48 · 2019: 36 · 2018: 45 · 2017: 34 · 2016: 46 · 2015: 46 · 2014: 37 · 2013: 32 · 2012: 11
FWCI: 4.15
Type: journal article
Language: en
Open access: closed
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (P50CA090578, R01CA135257)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: chemoresistance, targeted therapy resistance, resistance mechanisms, personalized medicine
MeSH terms: Antineoplastic Agents, Humans, Neoplasms, Drug Resistance, Neoplasm, Precision Medicine

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Circumventing cancer drug resistance in the era of personalized medicine

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