Alterations in Genes of the EGFR Signaling Pathway and Their Relationship to EGFR Tyrosine Kinase Inhibitor Sensitivity in Lung Cancer Cell Lines

Gandhi, Jeet; Zhang, Jianling; Xie, Yang; Soh, Junichi; Shigematsu, Hisayuki; Zhang, Wei; Yamamoto, Hiromasa; Peyton, Michael; Girard, Luc; Lockwood, William W.; Lam, Wan L.; Varella‐Garcia, Marileila; Minna, John D.; Gazdar, Adi F.

doi:10.1371/journal.pone.0004576

Cited by 182 publications

(195 citation statements)

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“…For example, subsets of NSCLC have oncogenic mutations in EGFR, KRAS, BRAF, PIK3CA, or HER2 or a translocation involving the ALK gene. [17][18][19] In the more molecularly heterogeneous cancers, mutations in proteins other than the intended therapeutic target can profoundly affect response to therapy. Thus, in the case of EGFR inhibitor therapy in lung and colon cancer, KRAS and BRAF mutations strongly predict drug resistance.…”

Section: 5-16mentioning

confidence: 99%

Multiplex Mutation Screening by Mass Spectrometry

Beadling

Heinrich

Warrick

et al. 2011

The Journal of Molecular Diagnostics

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There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry-based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broadspectrum, prospective genotyping approach to personalized cancer medicine. The identification of somatic mutations that cause aberrant activation of intracellular signaling pathways has transformed the diagnosis and treatment of cancer. Mutations in specific genes define distinct subtypes of cancer, and provide invaluable markers for disease diagnosis and prognosis. Many of the mutated proteins also represent targets for novel therapeutic agents that are more specific, more efficacious, and less toxic than broad-based chemotherapeutic regimens.1-5 Indeed, matching the right drug to the right cancer genotype is a proven model for improving treatment and outcome in patients with chronic myelogenous leukemia (CML), nonsmall-cell lung carcinoma (NSCLC), gastrointestinal stromal tumor (GIST), colorectal carcinoma, and, most recently, malignant melanoma. 2,5-16The major successes from this therapeutic approach have been in diseases in which there is limited molecular heterogeneity, with all or most cases having a drug-sensitive mutation. Prime examples include BCR-ABL in CML 9 and KIT in GIST. 3,7 There is increasing evidence that many common cancers similarly harbor potentially druggable targets, albeit at relatively lower frequencies. For example, subsets of NSCLC have oncogenic mutations in EGFR, KRAS, BRAF, PIK3CA, or HER2 or a translocation involving the ALK gene. [17][18][19] In the more molecularly heterogeneous cancers, mutations in proteins other than the intended therapeutic target can profoundly affect response to therapy. Thus, in the case of EGFR inhibitor therapy in lung and colon cancer, KRAS and B...

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Section: 5-16mentioning

confidence: 99%

Multiplex Mutation Screening by Mass Spectrometry

Beadling

Heinrich

Warrick

et al. 2011

The Journal of Molecular Diagnostics

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“…[8][9][10] The incomplete dominance of the mutant allele over the wild-type allele may result from selective amplification of the mutant allele (partial MASI) and is likely to be identified by fluorescence in situ hybridization (FISH). In some cases, the mutant allele may be predominant in the absence of the wild-type allele (complete MASI), a phenomenon most likely to arise through acquired uniparental disomy.…”

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confidence: 99%

KRAS mutant allele-specific imbalance in lung adenocarcinoma

et al. 2011

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The significance of KRAS mutant allele-specific imbalance (MASI) in lung adenocarcinomas is unknown. KRAS MASI was defined as predominance of the mutant allele over the wild-type allele. We assessed the frequency of KRAS MASI by comparing peak heights of mutant and wild-type alleles on sequencing electropherograms and by KRAS fluorescence in situ hybridization (FISH). A review of sequencing electropherograms of 207 KRAS-mutated lung adenocarcinomas demonstrated 23 (11%) cases with the mutant allele peak higher than the wild-type allele peak and 15 (7%) cases with the mutant allele peak equal to the wild-type allele peak. Of 17 cases with the mutant allele peak higher or equal to the wild-type allele peak, 8 (47%) showed KRAS amplification by FISH. KRAS FISH analysis of 36 KRAS-mutated lung adenocarcinomas with the mutant allele peak lower than the wild-type allele peak, 21 KRAS and EGFR wild-type and 16 EGFR-mutated adenocarcinomas showed no KRAS amplification. KRAS MASI was associated with selective amplification of the KRAS mutant allele (Po0.001). Patients with KRAS MASI showed worse overall survival. The cumulative proportion surviving at 17 months for KRAS MASI group was 35% compared with 84.1% for patients with KRAS mutant allele peak lower than wild-type allele peak (P ¼ 0.012). The adverse prognostic significance of KRAS MASI was independent of clinical stage and was maintained among stage I patients. The detection of KRAS MASI in lung adenocarcinomas by sequencing electropherograms may identify patients with more aggressive disease.

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“…Non-small-cell lung cancer tumours with activating mutations of EFGR (the gene for epidermal growth factor receptor) demonstrate enhanced sensitivity to the effects of the oral tyrosine kinase inhibitors (tkis) gefitinib and erlotinib [7][8][9][10][11][12][13][14] . In a phase iii trial in East Asian lung adenocarcinoma patients enriched for the occurrence of EFGR mutations, progression-free survival (pfs) was superior for patients treated with gefitinib compared with those treated with carboplatin-paclitaxel 11 .…”

Section: Resultsmentioning

confidence: 99%