<i>EGFR</i>Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

Kobayashi, Susumu; Boggon, Titus J.; Dayaram, Tajhal; Jänne, Pasi A.; Kocher, Olivier; Meyerson, Matthew; Johnson, Bruce E.; Eck, Michael J.; Tenen, Daniel G.; Halmos, Balázs

doi:10.1056/nejmoa044238

Cited by 3,664 publications

(2,940 citation statements)

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“…Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance. 182 The same mutation was confirmed by Pao et al 208 through molecular analysis of EGFR in patients with acquired resistance to gefitinib or erlotinib. These gefitinib-resistant cases contain the same secondary mutation (T790M) in the kinase domain as those reported by Kobayashi et al 182 Codon 790 of EGFR is considered to be the 'gatekeeper' residue, which is an important determinant of inhibitor affinity in the ATP-binding pocket of EGFR.…”

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 77%

“…182 The same mutation was confirmed by Pao et al 208 through molecular analysis of EGFR in patients with acquired resistance to gefitinib or erlotinib. These gefitinib-resistant cases contain the same secondary mutation (T790M) in the kinase domain as those reported by Kobayashi et al 182 Codon 790 of EGFR is considered to be the 'gatekeeper' residue, which is an important determinant of inhibitor affinity in the ATP-binding pocket of EGFR. 110 Substitution of this residue in EGFR with a bulky methionine may cause resistance by steric interference with binding of TKIs, including gefitinib and erlotinib.…”

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 77%

“…67 Moreover, the appearance of a secondary mutation in exon 20 (T790M) accounts for B50% of acquired drug resistance. 71,182 Screening for the emergence of such mutations on circulating tumor cells from the blood of patients during the course of treatment may allow earlier identification of acquired resistance. 178,180 Other TKI-resistant mutations include insertions in D770 at exon 20 and D761Y at exon 19 ( Figure 2).…”

Section: Mechanisms Of Resistance To Egfr Targeted Therapymentioning

confidence: 99%

“…110 Substitution of this residue in EGFR with a bulky methionine may cause resistance by steric interference with binding of TKIs, including gefitinib and erlotinib. 182,208,243 This mutation confers a survival advantage to the tumor and is selected while the patient is receiving anti-EGFR TKI treatment. 82,179 This secondary mutation is quite prevalent, being found in up to 50% of EGFR-mutant tumors treated with first-generation EGFR TKIs.…”

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 99%

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Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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Section: Acquired Resistance To Egfr Tkimentioning

confidence: 77%

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 77%

Section: Mechanisms Of Resistance To Egfr Targeted Therapymentioning

confidence: 99%

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 99%

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Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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“…It would be a primary reason of failure to some extent 63. Besides, the EGFR T790M mutation could be another important mechanism for resistance to EGFR TKIs 64. Repeated biopsy showed that it may be responsible for half of acquired resistance cases 65.…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

835

697

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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EGFRMutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

Cited by 3,664 publications

References 23 publications

Molecular pathology of lung cancer: key to personalized medicine

Molecular pathology of lung cancer: key to personalized medicine

Emerging findings into molecular mechanism of brain metastasis

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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