Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma

The advent of genomics has led to the identification of specific “driver” mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance.

• Publication year

  2017

• Venue

  npj Precision Oncology

• Publication date

  2017-03-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41698-017-0007-0PMID 29152593PMCID 5687582
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

  2016cited by this paper
• Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib.

  2016cited by this paper
• Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA

  2016cited by this paper
• Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

  2016cited by this paper
• Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells

  2016cited by this paper
• Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.

  2016cited by this paper
• Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.

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• Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor‐tyrosine kinase inhibitor in lung cancer

  2016cited by this paper
• EMT is associated with, but does not drive resistance to ALK inhibitors among EML4‐ALK non‐small cell lung cancer

  2016cited by this paper
• Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

  2016cited by this paper
• A framework for understanding and targeting residual disease in oncogene-driven solid cancers

  2016cited by this paper
• Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas

  2015cited by this paper
• Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M

  2015cited by this paper
• Studying clonal dynamics in response to cancer therapy using high-complexity barcoding

  2015cited by this paper
• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.

  2015cited by this paper
• Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.

  2015cited by this paper
• RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

  2015cited by this paper
• Crizotinib in ROS1-rearranged non-small-cell lung cancer.

  2015cited by this paper
• Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.

  2015cited by this paper
• The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

  2015cited by this paper
• Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.

  2015cited by this paper
• A functional landscape of resistance to ALK inhibition in lung cancer.

  2015cited by this paper
• NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer.

  2015cited by this paper
• RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer

  2015cited by this paper
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  2014cited by this paper
• Crizotinib in ROS1-rearranged non-small-cell lung cancer.

  2014cited by this paper
• Rationale for co-targeting IGF-1R and ALK in ALK fusion positive lung cancer

  2014cited by this paper
• Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.

  2014cited by this paper
• Ceritinib in ALK-rearranged non-small-cell lung cancer.

  2014cited by this paper
• Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor

  2014cited by this paper
• Ceritinib in ALK-rearranged non-small-cell lung cancer.

  2014cited by this paper
• KRAS and YAP1 converge to regulate EMT and tumor survival.

  2014cited by this paper
• Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.

  2014cited by this paper
• Tumour heterogeneity and the evolution of polyclonal drug resistance

  2014cited by this paper
• Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

  2014cited by this paper
• Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.

  2013cited by this paper
• The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents.

  2013cited by this paper
• Epithelial‐mesenchymal transition leads to crizotinib resistance in H2228 lung cancer cells with EML4‐ALK translocation

  2013cited by this paper
• The quest to overcome resistance to EGFR-targeted therapies in cancer

  2013cited by this paper
• Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway.

  2013cited by this paper
• Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

  2012cited by this paper
• Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung Cancer

  2012cited by this paper
• Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer

  2012cited by this paper
• Melanoma whole exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance

  2012cited by this paper
• Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.

  2012cited by this paper
• Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

  2012cited by this paper
• Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.

  2012cited by this paper
• HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.

  2012cited by this paper
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  2012cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2010cited by this paper
• A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

  2010cited by this paper
• RAF inhibitors transactivate RAF dimers and ERK signaling in cells with wild-type BRAF

  2010influential reference
• Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies

  2010cited by this paper
• PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.

  2009cited by this paper
• MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients.

  2009cited by this paper
• Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis

  2009cited by this paper
• Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with EGFR-Mutant Lung Adenocarcinoma

  2008cited by this paper
• Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.

  2008cited by this paper
• The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

  2008cited by this paper
• Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a "never-smoked" female patient with advanced non-small cell lung cancer.

  2007cited by this paper
• MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

  2007cited by this paper
• MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib

  2007cited by this paper
• Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer.

  2006cited by this paper
• EGFR mutations in small-cell lung cancers in patients who have never smoked.

  2006cited by this paper
• Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors

  2006cited by this paper
• ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.

  2005cited by this paper
• EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.

  2005cited by this paper
• Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain

  2005cited by this paper
• Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib).

  2005cited by this paper
• Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

  2005cited by this paper
• Anticancer drugs: To the rescue?

  2004cited by this paper
• Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

  2004cited by this paper

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• Epigenetics and companion diagnostics: opportunities and challenges.

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• Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

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• Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

  2023cites this paper
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  2023cites this paper
• Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

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• Predicting Anticancer Drug Resistance Mediated by Mutations

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• Impact of ecDNA: A mechanism that directs tumorigenesis in cancer drug Resistance-A review.

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• SPLDExtraTrees: Robust machine learning approach for predicting kinase inhibitor resistance

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  2019cites this paper
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  2018cites this paper
• Network Propagation Predicts Drug Synergy in Cancers.

  2018cites this paper
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  2018cites this paper
• Identifying small molecule probes of ENTPD5 through high throughput screening

  2018cites this paper
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