Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients

Yashima,Hideaki; Shimizu,Kimihiro; Araki,Takuya; Aomori,Tohru; Ohtaki,Yoichi; Nagashima,Toshiteru; Enokida,Yasuaki; Atsumi,Jun; Nakamura,Tomonori; Takeyoshi,Izumi; Yamamoto,Koujirou

doi:10.3892/mco.2014.302

Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients

Authors:
- Hideaki Yashima
- Kimihiro Shimizu
- Takuya Araki
- Tohru Aomori
- Yoichi Ohtaki
- Toshiteru Nagashima
- Yasuaki Enokida
- Jun Atsumi
- Tomonori Nakamura
- Izumi Takeyoshi
- Koujirou Yamamoto
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Affiliations: Department of Clinical Pharmacology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan, Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Published online on: June 3, 2014 https://doi.org/10.3892/mco.2014.302
Pages: 714-718

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Abstract

Molecular‑targeted therapy has not been established in non-adenocarcinoma lung cancer (non-AdLC), as no targets that affect the clinical efficacy of molecular‑targeted drugs have yet been identified. In this study, we investigated the frequency of genetic variations in discoidin domain receptor 2 (DDR2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR) and v-Ki‑ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in non‑AdLC patients, in order to evaluate the possibility of genetic mutations in these genes being used as therapeutic targets for the treatment of patients with non‑AdLC. For this purpose, we enrolled 150 non-AdLC patients who had undergone surgery at the Gunma University Hospital between December, 2003 and December, 2012. Genetic mutations in the EGFR, KRAS, DDR2 and BRAF genes were detected by a sequencing method or probe assay using DNA derived from cancer tissues. No somatic mutations in DDR2 or BRAF were detected in non-AdLC patients. Conversely, genetic mutations in EGFR exon 19 were found in 3 squamous cell carcinoma (SCC) and 3 adenosquamous carcinoma patients, whereas KRAS codon 12 mutations were also found in 3 SCC patients and 1 large‑cell neuroendocrine carcinoma patient. EGFR and KRAS mutations were mutually exclusive. This study indicated that, although DDR2 and BRAF mutations may only rarely be used as therapeutic targets, EGFR and KRAS mutations may represent candidate therapeutic targets, at least in the non-AdLC patients investigated.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 26:3543–3551. 2008. View Article : Google Scholar : PubMed/NCBI
3	Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 346:92–98. 2002. View Article : Google Scholar
4	Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 355:2542–2550. 2006. View Article : Google Scholar : PubMed/NCBI
5	Sun Y, Ren Y, Fang Z, et al: Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol. 28:4616–4620. 2010. View Article : Google Scholar : PubMed/NCBI
6	Gaughan EM and Costa DB: Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol. 3:113–125. 2011. View Article : Google Scholar : PubMed/NCBI
7	Toyooka S, Yatabe Y, Tokumo M, et al: Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung. Int J Cancer. 118:1588–1590. 2006. View Article : Google Scholar : PubMed/NCBI
8	Iwanaga K, Sueoka-Aragane N, Nakamura T, Mori D and Kimura S: The long-term survival of a patient with adenosquamous lung carcinoma harboring EGFR-activating mutations who was treated with gefitinib. Intern Med. 51:2771–2774. 2012. View Article : Google Scholar : PubMed/NCBI
9	Marchetti A, Martella C, Felicioni L, et al: EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 23:857–865. 2005. View Article : Google Scholar
10	Rekhtman N, Paik PK, Arcila ME, et al: Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167–1176. 2012. View Article : Google Scholar : PubMed/NCBI
11	Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 137:828–860. 2013.
12	Haura EB, Tanvetyanon T, Chiappori A, et al: Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer. J Clin Oncol. 28:1387–1394. 2010. View Article : Google Scholar : PubMed/NCBI
13	Hammerman PS, Sos ML, Ramos AH, et al: Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 1:78–89. 2011. View Article : Google Scholar : PubMed/NCBI
14	Valiathan RR, Marco M, Leitinger B, Kleer CG and Fridman R: Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 31:295–321. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ding L, Getz G, Wheeler DA, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 455:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
16	Davies H, Hunter C, Smith R, et al: Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 65:7591–7595. 2005.PubMed/NCBI
17	An SJ, Chen ZH, Su J, et al: Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status. PLoS One. 7:e401092012. View Article : Google Scholar : PubMed/NCBI
18	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
19	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
20	Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 101:13306–13311. 2004.
21	Calvo E and Baselga J: Ethnic differences in response to epidermal growth factor receptor tyrosine kinase inhibitors. J Clin Oncol. 24:2158–2163. 2006. View Article : Google Scholar : PubMed/NCBI
22	Sasaki H, Shitara M, Yokota K, et al: DDR2 polymorphisms and mRNA expression in lung cancers of Japanese patients. Oncol Lett. 4:33–37. 2012.PubMed/NCBI
23	Miyamae Y, Shimizu K, Hirato J, et al: Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep. 25:921–928. 2011.PubMed/NCBI
24	Araki T, Shimizu K, Nakamura T, et al: Clinical screening assay for EGFR exon 19 mutations using PNA-clamp smart amplification process version 2 in lung adenocarcinoma. Oncol Rep. 26:1213–1219. 2011.PubMed/NCBI
25	Araki T, Shimizu K, Nakamura K, et al: Usefulness of peptide nucleic acid (PNA)-clamp smart amplification process version 2 (SmartAmp2) for clinical diagnosis of KRAS codon 12 mutations in lung adenocarcinoma: comparison of PNA-clamp SmartAmp2 and PCR-related methods. J Mol Diagn. 12:118–124. 2010. View Article : Google Scholar
26	Ali BR, Xu H, Akawi NA, et al: Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum Mol Genet. 19:2239–2250. 2010. View Article : Google Scholar : PubMed/NCBI
27	Iyoda A, Travis WD, Sarkaria IS, et al: Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. Exp Ther Med. 2:1041–1045. 2011.PubMed/NCBI
28	Tanaka K, Hata A, Kida Y, et al: Gefitinib for a poor performance status patient with squamous cell carcinoma of the lung harboring EGFR mutation. Intern Med. 51:659–661. 2012. View Article : Google Scholar : PubMed/NCBI
29	Zhou C, Wu YL, Chen G, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
30	Jänne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 14:38–47. 2013.PubMed/NCBI
31	Sequist LV, von Pawel J, Garmey EG, et al: Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol. 29:3307–3315. 2011. View Article : Google Scholar : PubMed/NCBI
32	Sakurai H, Asamura H, Watanabe S, Suzuki K and Tsuchiya R: Clinicopathologic features of peripheral squamous cell carcinoma of the lung. Ann Thorac Surg. 78:222–227. 2004. View Article : Google Scholar : PubMed/NCBI
33	Drilon A, Rekhtman N, Ladanyi M and Paik P: Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 13:e418–e426. 2012. View Article : Google Scholar : PubMed/NCBI
34	Montero JC, Seoane S, Ocaña A and Pandiella A: Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res. 17:5546–5552. 2011. View Article : Google Scholar : PubMed/NCBI