Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer

Linardou, Helena; Dahabreh, Issa J; Kanaloupiti, D.; Siannis, Fotios; Bafaloukos, Dimitrios; Kosmidis, P.; Papadimitriou, Christos; Murray, Samuel

doi:10.1016/s1470-2045(08)70206-7

Cited by 684 publications

(494 citation statements)

References 85 publications

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“…[38][39][40] Mutations in KRAS or PIK3CA are associated with nonresponsiveness to anti-EGFR therapy. 41,42 Our study indicated that in the case of serous cystic neoplasms, overexpression of the EGFR protein with increased copy number of EGFR transcripts occurs without amplification of the EGFR gene. The serous cystic neoplasms did not show any mutations in exons 18-23 of EGFR, which encode the kinase domain, nor in any of the examined hot spots in KRAS, BRAF, or PIK3CA.…”

Section: Discussionmentioning

confidence: 69%

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas

Kuboki

Shiratori²,

Hatori³

et al. 2010

Modern Pathology

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The molecular pathobiology of pancreatic cystic neoplasms is poorly understood. The aim of this study was to know the involvement of epidermal growth factor receptor (EGFR) and its downstream targets in the serous cystic neoplasms and the mucinous cystic neoplasms of the pancreas. In a total of 72 pancreatic cystic neoplasms, including 39 serous cystic neoplasms and 33 mucinous cystic neoplasms, we examined the expression of native and phosphorylated EGFR, mitogen-activated protein kinase (MAPK), and AKT by immunohistochemistry and somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, by direct sequencing. We also assessed the copy numbers of EGFR transcripts and the amplification of the EGFR gene in some of the samples. We found that EGFR, phosphorylated EGFR, MAPK, and phosphorylated MAPK were evidently expressed in 100, 54, 100, and 69% of the serous cystic neoplasms, and in 12%, none, 33, and 27% of the mucinous cystic neoplasms, respectively; the expression was significantly higher and more prevalent in the serous cystic neoplasms than in the mucinous cystic neoplasms. The expression of AKT and phosphorylated AKT was low in both the types of neoplasms. On average, EGFR transcripts in the serous cystic neoplasms and the mucinous cystic neoplasms increased 53.5-and 2.5-fold, respectively, as compared with that in normal tissues, with the increase in the former being significantly greater than that in the latter. Amplification of the EGFR gene was not detected in any of the examined serous cystic neoplasms. None of the tumors had mutations in any of the examined portions of the genes, except two mucinous cystic neoplasms with mutations in codon-12 of KRAS. These results indicate that EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms and may therefore be potential diagnostic markers and therapeutic targets in patients with the above mentioned types of neoplasms.

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Section: Discussionmentioning

confidence: 69%

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas

Kuboki

Shiratori²,

Hatori³

et al. 2010

Modern Pathology

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“…205,206 KRAS mutation is a negative predictor of response to anti-EGFR monoclonal antibodies and is also an important mechanism of resistance to TKIs in lung adenocarcinomas. 55 A meta-analysis by Linardou et al 207 provided empirical evidence that somatic mutations of the KRAS oncogene are highly specific negative predictors of response to single-agent EGFR TKIs in advanced lung cancers, mostly adenocarcinomas. Mao et al 121 reviewed 1470 lung cancers from 22 publications, of which 231 had KRAS mutations (16%).…”

Section: Kras Mutationsmentioning

confidence: 99%

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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“…[3][4][5] Other mutually exclusive mutations and negative predictors to EGFR-TKI, such as KRAS and BRAF mutations, represent alternative mechanisms of activating the MAP kinase pathway in lung adenocarcinomas. 6,7 Previously unknown markers, such as noncoding RNA gene products, may be important contributors to lung cancer development as well. MicroRNA (miRNA) is a group of endogenous, small, noncoding RNA that can modulate protein expression by regulating translational efficiency or cleavage of target.…”

mentioning

confidence: 99%

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

et al. 2010

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MicroRNA (miRNA) expression is deregulated in lung cancer, and some miRNAs are associated with poor prognosis and survival. In this study, we investigated the miRNA expression in lung adenocarcinomas with different oncogenic mutations, including EGFR-positive, KRAS-positive and EGFR/KRAS-negative tumors. The expression of 319 miRNAs was evaluated by Exiqon/Luminex microarray, and expression of individual miRNAs was validated by individual RT-PCR assays (Applied Biosystems). Overall, miRNA expression was similar among three mutationally different groups with most upregulated miRNAs being miR-20a, miR-328, miR-34c and miR-18b and most downregulated miRNAs being miR-32, miR-137 and miR-342. Four miRNAs (miR-155, miR-25, miR-495 and miR-7g) were expressed differently among these tumors. miR-155 was upregulated only in EGFR/KRAS-negative group, miR-25 was upregulated only in EGFR-positive group and miR-495 was upregulated only in KRAS-positive adenocarcinomas. In opposite, let-7g was downregulated in all three groups, with more significant downregulation in EGFR/KRASnegative adenocarcinomas. Principal component analysis (PCA) revealed significant correlation between miRNA expression patterns and somatic mutations. In this study, we demonstrated that despite the similarity in miRNA expression among lung adenocarcinomas with different somatic mutations, some miRNAs showed unique expression patterns, which were in strong correlation with the mutation type, suggesting different carcinogenic pathway for these tumors. These miRNAs can be further explored for their diagnostic and prognostic use.

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Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer

Cited by 684 publications

References 85 publications

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas

Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas

Molecular pathology of lung cancer: key to personalized medicine

miRNA expression profiling of lung adenocarcinomas: correlation with mutational status

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