Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib

Tartarone, Alfredo; Lazzari, Chiara; Lerose, Rosa; Conteduca, Vincenza; Improta, Giuseppina; Zupa, Angela; Bulotta, Alessandra; Aieta, Michele; Gregorc, Vanesa

doi:10.1016/j.lungcan.2013.05.020

Cited by 47 publications

(42 citation statements)

References 86 publications

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“…For instance, tyrosine kinase inhibitors (TKI) have proved effective in patients with metastatic tumors that harbor the mutated EGFR gene (2,3), whereas the presence of mutations in the KRAS gene has been proposed to correlate with resistance to treatment with TKI (4,5). However, the number of patients for whom targeted therapy is available is small, and it is becoming clear that effects of these therapies may not always be long lasting due to the development of resistance (6,7). Therefore, additional therapeutic approaches are urgently needed both for treating larger numbers of patients, including those with earlystage disease, and for inducing stable clinical responses and extended survival.…”

Section: Introductionmentioning

confidence: 99%

Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS

Ayyoub

Memeo

Álvarez-Fernández

et al. 2014

Cancer Immunology Research

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Non-small cell lung cancer (NSCLC) is a major public health problem, accounting for more cancer-related deaths than any other cancer. Both immunotherapy, based on the expression of tumor-specific antigens, and targeted therapy, based on the presence of oncogenic mutations, are under development for NSCLC. In this study, we analyzed the expression of MAGE-A, a cancer-testis antigen, in tumors from a cohort of patients with resected NSCLC with respect to their clinicopathologic characteristics and their mutational status for the EGFR and KRAS genes. We found MAGE-A expression by IHC in 43% of the tumors. MAGE-A expression was significantly more frequent in squamous tumors than in adenocarcinomas, did not correlate with disease stage, but was correlated significantly with high tumor grade and worse survival. EGFR and KRAS mutations were present in adenocarcinomas, but not in squamous tumors. Whereas the presence of EGFR mutations did not seem to affect survival, the presence of KRAS mutations was associated with early-stage disease and better survival. MAGE-A expression was absent from adenocarcinomas with KRAS mutations, but not significantly different in tumors with or without EGFR mutations. Together, the reported results provide guidance for the design of combination therapies in patients with NSCLC. Cancer Immunol Res; 2(10); 943-8. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS

Ayyoub

Memeo

Álvarez-Fernández

et al. 2014

Cancer Immunology Research

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“…The predictors of clinical response to EGFR TKIs [9], mechanisms of drug resistance and potential strategies to overcome resistance [10][11][12] have been reviewed elsewhere and detailed discussion of these is beyond the scope of this review.…”

Section: Pharmacodynamic Propertiesmentioning

confidence: 99%

“…The T790M mutation and MET amplification are the most common acquired resistance mechanisms, accounting for ≈60 % of cases [11]. Approximately 50 % of EGFR TKIresistant patients have been found to have the T790M mutation (substitution of threonine to methionine at codon 790, the gatekeeper residue) [11], which is thought to alter the proper binding of the drug to the ATP-binding site of EGFR and restores ATP affinity to the level of wild-type EGFR [10,11,39].…”

Section: Drug Resistancementioning

confidence: 99%

“…Approximately 50 % of EGFR TKIresistant patients have been found to have the T790M mutation (substitution of threonine to methionine at codon 790, the gatekeeper residue) [11], which is thought to alter the proper binding of the drug to the ATP-binding site of EGFR and restores ATP affinity to the level of wild-type EGFR [10,11,39]. Overexpression of MET (a transmembrane tyrosine kinase receptor that binds to hepatocyte growth factor) is seen in ≈20 % of patients with acquired resistance [11] and is thought to result in the persistent activation of the downstream phosphoinositide 3-kinase/AKT pathway, thereby overcoming EGFR-induced inhibition [10,11,38].…”

Section: Drug Resistancementioning

confidence: 99%

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Gefitinib: a review of its use in adults with advanced non-small cell lung cancer

Dhillon

2015

Targ Oncol

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Gefitinib (Iressa®) is a selective small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR TKI) indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR tyrosine kinase. Large phase III or IV clinical trials in patients with locally advanced or metastatic NSCLC showed that gefitinib as first- or subsequent-line treatment significantly prolonged progression-free survival (PFS) and improved objective response rates and/or health-related quality of life parameters in patients with activating EGFR mutations and in clinically selected patients (e.g., Asian patients or never-smokers) who are more likely to harbour these mutations. Overall survival did not increase significantly with gefitinib, although post-study treatments may have had a confounding effect on this outcome. Gefitinib was generally well tolerated in these studies, with mild or moderate skin reactions, gastrointestinal disturbances and elevations in liver enzymes among the most common adverse reactions in gefitinib recipients; interstitial lung disease has also been reported in <6 % of gefitinib recipients. Compared with chemotherapy, gefitinib as first- or subsequent-line therapy provided similar or greater PFS benefit and was generally associated with fewer haematological adverse events, neurotoxicity, asthenic disorders, as well as grade ≥3 adverse events. Although the position of gefitinib with respect to other EGFR TKIs is not definitively established, current evidence indicates that gefitinib monotherapy is an effective and generally well-tolerated first- or subsequent-line treatment option for patients with NSCLC and activating EGFR mutations who have not received an EGFR TKI previously.

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“…However, in the last decade, several biological agents targeting specific molecular alterations, including gefitinib or erlotinib targeting epidermal growth factor receptor (EGFR) mutations and crizotinib targeting anaplastic lymphoma kinase (ALK) translocations, have been approved for clinical use and used in personalized treatment regimes (3)(4)(5)(6)(7). Selected molecular-targeted therapy for BM of lung cancer has been notably effective, demonstrated by response rates, progression-free survival and quality of life in small studies and case reports (8)(9)(10)(11); however, there are limited data available regarding the differential genetic aberrations between lung adenocarcinoma BM (LCBM) and primary lung cancer (LC) (12).…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing reveals distinct pathogenic variants in Chinese patients with lung adenocarcinoma brain metastases

Chen

Yang³

et al. 2018

Oncol Lett

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Abstract. Lung cancer is the most common type of malignancy to metastasize to the brain, with the median survival time of patients being 6-11 months. In the present study, the aim was to compare the actionable gene mutation profiles of primary lung adenocarcinoma (LC) samples and LC brain metastasis (LCBM) samples through targeted sequencing. Next generation sequencing (NGS) of 13 formalin-fixed, paraffin-embedded LC samples and 15 LCBM samples was performed using a customized OncoAim™ cancer panel and OncoAim™ RNA fusion panel on the MiSeq platform. The OncoAim™ cancer panel pipeline and OncoAim™ RNA fusion panel pipeline were used for bioinformatic analysis. Together, 43 variants were observed in 7 genes from the 28 cancer samples. The mutated genes of LCBM were tumor protein (TP)53, epidermal growth factor receptor (EGFR), catenin β1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, mothers against decapentaplegic homolog 4, Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene B-Raf, which were exhibited in 10/15 (66.7%), 6/15 (40.0%), 3/15 (20.0%), 2/15 (13.3%), 2/15 (13.3%), 1/15 (6.7%) and 1/15 (6.7%) of samples, respectively. The mutated genes of LC were TP53, EGFR and KRAS, which were exhibited in 11/13 (84.6%), 5/13 (38.5%) and 2/13 (18.2%) of samples, respectively. echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase rearrangements were present in 1 LCBM sample. For 2 LC samples and 1 LCBM sample, no genetic alterations were observed. The NGS data also revealed a novel 4-codon deletion of TP53 (p.V166_H169del) and a novel TP53 splice site mutation (7577157-63del TACTCAG). Further potentially actionable mutations were detected in LCBM, indicating a high degree of genetic heterogeneity between the LC and LCBM samples that were analyzed. The present study demonstrated that NGS provides an improved approach for the discovery of potentially actionable mutations and the understanding of the mechanisms underlying tumor progression and evolution.

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Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib

Cited by 47 publications

References 86 publications

Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS

Assessment of MAGE-A Expression in Resected Non–Small Cell Lung Cancer in Relation to Clinicopathologic Features and Mutational Status of EGFR and KRAS

Gefitinib: a review of its use in adults with advanced non-small cell lung cancer

Targeted sequencing reveals distinct pathogenic variants in Chinese patients with lung adenocarcinoma brain metastases

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