EGFR and KRAS Mutations in Patients With Adenocarcinoma of the Lung

Jang, Tae Won; Oak, Chulho; Chang, Hee Kyung; Suo, Soon Jung; Jung, Mann Hong

doi:10.3904/kjim.2009.24.1.48

Cited by 63 publications

(36 citation statements)

References 24 publications

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“…This observation is consistent with other studies showing that the frequencies of KRAS mutations vary with ethnicity [77][78][79][80] . G12D was the most frequent KRAS transition mutation found …”

Section: Dependency Of Ral Activity On Ras Mutationsupporting

confidence: 82%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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Section: Dependency Of Ral Activity On Ras Mutationsupporting

confidence: 82%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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“…Recently, it was found that EGFR mutation was a sensitive marker of NSCLC to EGFR TKI drugs, while KRAS mutation was a resistant one [22,23]. Considering the incidence of gene mutations including EGFR and KRAS in NSCLC varied regionally and racially, we detected EGFR and KRAS mutations in 157 NSCLC patients from mainland China, and found that the mutation frequencies of EGFR and KRAS were both similar to reports from other East Asia areas, such as Taiwan China, Japan and Korea [19,[24][25][26][27][28]. Comparing to western countries, the mutation frequency of EGFR was higher, while that of KRAS was lower in the East Asia areas [20,29,30].…”

Section: Discussionmentioning

confidence: 70%

The different clinical significance of EGFR mutations in exon 19 and 21 in non-small cell lung cancer patients of China

Zhang²,

Liu³

et al. 2011

neo

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Mutations of epithelial growth factor receptor (EGFR) in exon 19 and 21 are both believed to be associated with carcinogenesis, sensitivity to tyrosine kinase drugs and with the prognosis of non-small cell lung cancers (NSCLCs). However, their exact clinical significance remains disputable. We detected the mutations of 157 NSCLCs from mainland China with high resolution melting analysis and identified exon mutations with DNA sequencing. Of the 157 cases examined, 57 displayed EGFR mutations which included 22 in exon 19 and 35 in exon 21. Current research has shown that EGFR mutations are more commonly associated with the female population and East Asians, with additional significance being adenocarcinomas. Our current findings are supporting this sugestion. We analysed the clinicalpathological characteristics of mutations in exon 19 and 21 separately, which showed that the mutation frequency of NSCLCs in exon 21, but not in exon 19, were significantly higher in females. Comparatively, mutation frequencies in exon 19 were significantly higher in the stage I and II than in the stage III abnd IV, while tumors with lymph node metastasis and the stage III and IV demonstrated significantly higher mutation frequencies in exon 21. Additionally, exon mutations in the left and right lung showed significant differences: with exon 19 mutations being more frequent in the tumors of left lung, and exon 21 mutuations showing a higher incidence in right lung tumors. This suggests that, in mainland China, NSCLCs with EGFR mutations in exon 19 could have a less malignant character than those with mutations in exon 21. It's the first report that EGFR mutations in exon 19 and exon 21 in NSCLC patients may relate to the tumor sites, but further research is still required.

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“…EGFR mutations were also reported in rarely seen types of NSCLC such as pleomorphic (15%), and also adenosquamous carcinomas (38%) (Jia and Chen, 2011;Lee et al, 2011). A South Korean study detected EGFR mutations in 24% of the cases with adenocarcinomas (Jang et al, 2009). EGFR mutations were also found in 9 of 33 cases with sarcomatoid carcinoma which is a rarely seen subtype (Jiang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Relationship between Epidermal Growth Factor Receptor Gene Mutations and Clinicopathological Features in Patients with Non-Small Cell Lung Cancer in Western Turkey

Ünal

Öztop²,

Çalıbaşı³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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EGFR and KRAS Mutations in Patients With Adenocarcinoma of the Lung

Cited by 63 publications

References 24 publications

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

The different clinical significance of EGFR mutations in exon 19 and 21 in non-small cell lung cancer patients of China

Relationship between Epidermal Growth Factor Receptor Gene Mutations and Clinicopathological Features in Patients with Non-Small Cell Lung Cancer in Western Turkey

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