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Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Open accessAbstract
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.
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“The third-generation drug retains the acrylamide group and covalently binds to Cys797, but replaces the quinazoline portion of the first- and second-generation compounds with pyrimidine to promote selectivity for T790M, showing a higher affinity for T790M than WT-EGFR.119”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [119]
In the citing paper
“Mutations in EGFR occur in 10-35% of NSCLCs and confer sensitivity to the EGFR TKIs erlotinib, gefitinib, and afatinib (6).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [6]
In the citing paper
“Exon 20 insertion mutations comprise 4–10% of all EGFR mutations 27,29–32.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [30]
In the citing paper
“Indeed, while ERBB2 gene amplifications and gain-of-function EGFR mutations support the proliferation of various cancer cell types (Oh and Bang, 2020; Pao and Chmielecki, 2010), VEGFA is critical for tumor-driven neoangiogenesis (Apte et al., 2019) and TGFb promotes the establishment of a fibrotic microenvironment that is poorly permissive to access by therapeutics (Derynck et al., 2020).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Pao and Chmielecki, 2010
In the citing paper
“Over the past two decades, a number of mAbs and TKIs have been developed to target these proteins or their binding partners, and some of these molecules, including HER2-, EGFR-, and VEGFA-specific agents, have been licensed for use in a variety of oncological indications (Apte et al., 2019; Oh and Bang, 2020; Pao and Chmielecki, 2010).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Pao and Chmielecki, 2010
In the citing paper
“EGFR mutations are primarily localized within two hot spots of the kinase domains, a series of overlapping deletions in exon 19 and a leucine to arginine substitution at amino acid position 858 (L858R) [reviewed in (Pao and Chmielecki, 2010)].”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Pao and Chmielecki, 2010
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“It took an unprecedented four years from the discovery of ALK rearrangement in NSCLC to the approval of crizotinib, the first ever ALK inhibitor, for the treatment of ALKrearranged NSCLC. Keywords: crizotinib, PF-02341066, anaplastic lymphoma kinase (ALK), rearrangement, non-small cell lung cancer Introduction During…”
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A framework for identification of actionable cancer genome dependencies in small cell lung cancer
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“NSCLC has become a prototype for personalized therapy in oncology because this disease, particularly the adenocarcinoma subtype, has been segmented by multiple oncogenic “driver” events such as EGFRactivating mutations and ALK and ROS fusions, each of which may be treated with unprecedented success by selected small-m…”
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“Recently, the presence of co-occurrence of EGFR and other gene lesions was reported to reduce the sensitivity of EGFR-TKI [42], and the addition of a constitutively active PI3K mutant has been shown to confer gefitinib resistance in vitro [43].”
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EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition
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Mechanism for activation of mutated epidermal growth factor receptors in lung cancer
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“The most frequent of these, which occur with a combined frequency of 90% (1), are exon 19 deletions that eliminate four amino acids (LREA) from the TKD and exon 21 missense mutations that substitute arginine for leucine at position 834 (L834R) (also identified as L858R in an alternative numbering of the human EGFR seq…”
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“EGFR is recognized as an oncogene driver in non–small cell lung cancer (NSCLC) because activating mutations in the kinase domain of EGFR cause an enhanced EGFR tyrosine kinase activity and a persistent activation of downstream signaling pathways that, in turn, drive oncogenesis and tumor progression (10).”
BackgroundVersatile role of curcumin and its derivatives in lung cancer therapy
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“Curcumin analog also has an inhibitory impact on EGFR that can be used in suppressing the malignancy of NSCLC cells (Shaik, Al‐Kreathy, Ajabnoor, Verma, & Banaganapalli, 2019).”
BackgroundInfluentialLung Cancer Subtypes Generate Unique Immune Responses
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“Although patients with EGFR mutations initially respond to targeted therapies, drug resistance typically develops within the first year (6).”
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“Although these mutations in EGFR are sensitive to inhibition by established tyrosine kinase inhibitor (TKI) therapies, such as gefitinib, erlotinib and icotinib, almost all tumors eventually develop acquired resistance to these TKIs within 9–14months [3, 5].”
BackgroundAnticancer metal drugs and immunogenic cell death
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“The EGFR gene is the most prevalent oncogenic driver in NSCLC, occurring in 10 – 15% of all NSCLC cases (21).”
BackgroundEmerging landscape of circular RNAs in lung cancer
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“In three phase III trials of Asian patients with EGFR mutations, median PFS was significantly longer in patients receiving gefitinib (9.2– 10.8 months) than in those receiving chemotherapy (5.4–6.3 months), with a significant improvement in the hazard ratios (HRs) for progression [estimates ranging from 0.30 to 0.48;…”
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Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition
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“NSCLC account for 82% of lung cancers (2).”
BackgroundResistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer
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“Treatment with these kinase inhibitor drugs results in improved efficacy and has more tolerable side effects compared to standard chemotherapies in patients who are pre-screened for the activating genetic alterations [5,6,7].”
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“34 On the other hand, T790M point mutation arises after the patient's initial responses to EGFR TKI treatment, indicating the development of resistance to EGFR TKIs 35 and the necessity of administering new-generation EGFR TKIs ( e.g. , AZD9291 36 and CO-1686 37 ).”
Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts
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“…EGFR inhibitors Although NSCLC patients with activating mutations (namely L858R) have high RRs to TKI therapies and show complete responses with dramatic tumor shrinkage, almost all patients acquire resistances to TKI therapies upon long-term CT (Pao and Chmielecki, 2010; Pao et al., 2005).”
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Alveolar Type II Cells Possess the Capability of Initiating Lung Tumor Development
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“Importantly, the L858R mutation in EGFR is frequently found in human adenocarcinoma and is known to confer ligand-independent EGF signaling [36,37].”
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Translating cancer ‘omics’ to improved outcomes: Figure 1.Preprint
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Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins
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“For example, acquisition of point mutations in the BCR–ABL and EGFR kinase domains that interfere with inhibitor binding frequently result in resistance to imatinib in chronic myeloid leukemia and to erlotinib in NSCLC, respectively (24, 25).”
BackgroundMolecular Pathology of Non–Small Cell Lung Cancer
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Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors
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“This pattern is akin to the clinical experience in EGFR-driven lung cancer, where type I TKIs such as erlotinib evoke dramatic but inevitably transient responses, funneling to common point mutation-based failure (47).”
BackgroundResult
Metadata
- Authors
- Pao, W., & Chmielecki, J.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Pao, William
- Venue
- Nature Reviews Cancer
- Published
- 2010-10-22
- Volume
- 10
- Issue
- 11
- Pages
- 760-774
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC3072803
- OpenAlex
- W2090029719
- Cited by
- 1,083
- References
- 180
- Citations by year
- 2026: 24 · 2025: 43 · 2024: 54 · 2023: 49 · 2022: 45 · 2021: 65 · 2020: 79 · 2019: 56 · 2018: 69 · 2017: 72 · 2016: 90 · 2015: 82 · 2014: 93 · 2013: 93 · 2012: 104
- FWCI
- 14.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute (P30 CA 68485, R01CA121210, P01CA129243, CA90949, U54CA143798, P50CA090949, P30CA068485)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR-mutant non-small cell lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitors, gefitinib, erlotinib, acquired drug resistance, primary resistance, targeted therapy
- MeSH terms
- Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Protein-Tyrosine Kinases, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors
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