Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung

Kim, Young Tae; Kim, Taeyou; Lee, Dong Hoon; Park, Sun Jung; Park, Ju Yeon; Seo, Soon-Jung; Choi, Hyo-Seon; Kang, Hee Jung; Hahn, Seokyung; Kang, Chang Hyun; Sung, Sook Whan; Kim, Joo Hyun

doi:10.1016/j.lungcan.2007.08.008

Cited by 90 publications

(81 citation statements)

References 25 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: 93%

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: 93%

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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“…Gender and smoking habits have been significantly related with EGFR mutations. 2,3,30,39 The commonly reported EGFR mutation rate by PCR sequencing and fragment analyses in lung adenocarcinomas is around 20%. 40 Mutations are found in the first four exons of the TK domain of the EGFR gene.…”

Section: Discussionmentioning

confidence: 99%

Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status

Sousa

Rodrigues

Silva

et al. 2015

Revista Portuguesa de Pneumologia (English Edition)

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Pulmonary adenocarcinomas are still in the process of achieving morphological, immunohistochemical and genetic standardization. The ATS/ERS/IASLC proposed classification for lung adenocarcinomas supports the value of the identification of histological patterns, specifically in biopsies.Thirty pulmonary adenocarcinomas were subjected to immunohistochemical study (CK7, CK5, 6, 18, CK20, TTF1, CD56, HER2, EGFR and Ki-67), FISH and PCR followed by sequencing and fragment analysis for EGFR, HER2 and KRAS.Solid pattern showed lower TTF1 and higher Ki-67 expression. TTF1 expression was higher in non-mucinous lepidic and micropapillary patterns when compared to acinar and solid and acinar, solid and mucinous respectively. Higher Ki67 expression was present in lepidic and solid patterns compared to mucinous. EGFR membranous staining had increasing expression from non-mucinous lepidic/BA pattern to solid pattern and micropapillary until acinar pattern. EGFR mutations, mainly in exon 19, were more frequent in females, together with non-smoking status, while KRAS exon 2 mutations were statistically more frequent in males, especially in solid pattern. FISH EGFR copy was correlated gross, with mutations. HER2 copy number was raised in female tumours without mutations, in all cases. Although EGFR and KRAS mutations are generally considered mutually exclusive, in rare cases they can coexist as it happened in one of this series, and was represented in acinar pattern with rates of 42.9% and 17.9%, respectively. EGFR mutations were more frequent in lepidic/BA and acinar patterns. Some cases showed different EGFR mutations.The differences identified between the adenocarcinoma patterns reinforce the need to carefully identify the patterns present, with implications in diagnosis and in pathogenic understanding. EGFR and KRAS mutational status can be determined in biopsies representing bronchial

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“…The frequency of EGFR mutation in adenocarcinoma showed wide variation among different reports (3-59.7%); this was related to ethnicity, gender, and smoking status [16][17][18][19][20]. Several studies, in which East Asia was the focus, have shown that the EGFR mutation rate in NSCLC was about 26-38.6%, and the mutation rate increased 32-55% in adenocarcinoma [16][17][18].…”

Section: Discussionmentioning

confidence: 97%

“…Several studies, in which East Asia was the focus, have shown that the EGFR mutation rate in NSCLC was about 26-38.6%, and the mutation rate increased 32-55% in adenocarcinoma [16][17][18]. However, there is a paucity of data regarding the EGFR mutation status in young patients (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Metastatic Adenocarcinoma in the Young Adult

Mehta¹,

Jain²,

Desai³

et al. 2017

Arch Surg Oncol

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We report a case of metastatic adenocarcinoma pleura in a non-smoking 29-year-old man. X-ray Chest revealed Left sided repeated pleural effusion despite repeated tapping. CT revealed a moderate Left sided pleural effusion. A VATS biopsy of the Left Pleural Nodules and Left lung nodules revealed a metastatic adenocarcinoma. He was a non-smoker and molecular markers revealed an EGFR Mutation and were started on oral TKI. He had near complete resolution after 6 months except for mild thickening of the pleura at the base.

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Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung

Cited by 90 publications

References 25 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

Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status

Metastatic Adenocarcinoma in the Young Adult

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