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; Abe, Jun; Nakamura, Tomonori; Takeyoshi, Izumi; Yamamoto, Keiji

doi:10.3892/mco.2014.302

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…In aseriesof 41 “histologically-pure” LCNECs, which are those tumors that do not contain other histologic components, EGFR and KRAS were evaluated by Sequenom, and 7 samples were found to harbor KRAS mutations. 43 EGFR/KRAS/DDR2/BRAF sequencing was performed in a second series of 11 patients with pure LCNEC, 44 and one KRAS mutation was noted. 44 Importantly, SCLC tumors do not harbor KRAS mutations.…”

Section: Discussionmentioning

confidence: 99%

“…43 EGFR/KRAS/DDR2/BRAF sequencing was performed in a second series of 11 patients with pure LCNEC, 44 and one KRAS mutation was noted. 44 Importantly, SCLC tumors do not harbor KRAS mutations. 43,45,46 Furthermore, genomic studies have demonstrated that subsets of LCNECs may harbor other alterations, seen in both adenocarcinomas and even squamous cell lung carcinomas.…”

Section: Discussionmentioning

confidence: 99%

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Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes

Naidoo

Santos-Zabala

Iyriboz

et al. 2016

Clinical Lung Cancer

128

106

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Clinical features and management of large cell neuroendocrine lung carcinoma of the lung are poorly described. We report a series of 49 patients with stage IV large cell neuroendocrine lung carcinomas; 47% had brain metastases. In 17 patients with molecular testing, 24% of tumors harbored KRAS mutations. Response to platinum/etoposide in these patients was poorer than historic data for small-cell lung cancer, however prognosis was similar. Background Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. Materials and Methods Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Results Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%–62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6–16.4 months) for the entire cohort. Conclusion Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes

Naidoo

Santos-Zabala

Iyriboz

et al. 2016

Clinical Lung Cancer

128

106

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“…Surgery, chemotherapy, radiotherapy, and targeted therapies are conventional lung cancer treatments [ 3 ]. Targeted therapies with tyrosine kinase inhibitors (TKIs) comprise epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib or gefitinib, and anaplastic lymphoma kinase (ALK) inhibitors, such as crizotinib [ 4 , 5 ]. Considering the high mortality and morbidity rates of lung cancer and the emergence of drug resistance to chemoradiotherapy regimens and TKIs, determining targetable genetic changes is of paramount importance [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further evaluations in Korea, China, and France populations revealed that the frequencies of DDR2 mutations were 2%, 4.6%, and 4% in SCC, respectively [ 10 – 12 ]. However, Kenmotsu et al and Yashima et al did not find any mutations in DDR2 gene of Japanese SCC patients [ 13 , 14 ]. In addition, despite the broader range of mutated genes in SCC, there is no effective targeted treatment for this subtype [ 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients

et al. 2018

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PurposeLung cancer is the deadliest known cancer in the world, with the highest number of mutations in proto-oncogenes and tumor suppressor genes. Therefore, this study was conducted to determine the status of hotspot regions in DDR2 and KRAS genes for the first time, as well as in TP53 gene, in lung cancer patients within the Iranian population.Experimental designThe mutations in exon 2 of KRAS, exon 18 of DDR2, and exons 5–6 of TP53 genes were screened in lung cancer samples, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using PCR and sequencing techniques.ResultsAnalysis of the KRAS gene showed only a G12C variation in one large cell carcinoma (LCC) patient, whereas variants were not found in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases. The Q808H variation in the DDR2 gene was detected in one SCC sample, while no variant was seen in the ADC and LCC subtypes. Variations in the TP53 gene were seen in all NSCLC subtypes, including six ADC (13.63%), seven SCC (15.9%) and two LCC (4.54%). Forty-eight variants were found in the TP53 gene. Of these, 15 variants were found in coding regions V147A, V157F, Q167Q, D186G, H193R, T211T, F212L and P222P, 33 variants in intronic regions rs1625895 (HGVS: c.672+62A>G), rs766856111 (HGVS: c.672+6G>A) and two new variants (c.560-12A>G and c.672+86T>C).ConclusionsIn conclusion, KRAS, DDR2, and TP53 variants were detected in 2%, 2.17% and 79.54% of all cases, respectively. The frequency of DDR2 mutation is nearly close to other studies, while KRAS and TP53 mutation frequencies are lower and higher than other populations, respectively. Three new putative pathogenic variants, for the first time, have been detected in Iranian patients with lung cancer, including Q808H in DDR2, F212L, and D186G in coding regions of TP53. In addition, we observed five novel benign variants, including Q167Q, P222P and T211T in coding sequence, and c.560-12A>G and c.672+86T>C, in intronic region of TP53. Mutations of KRAS and DDR2 were found in LCC and SCC subtypes, respectively, whereas mutations of TP53 were seen in SCC and ADC subtypes with higher frequencies and LCC subtype with lower frequency. Therefore, Iranian lung cancer patients can benefit from mutational analysis before starting the conventional treatment. A better understanding of the biology of these genes and their mutations will be critical for developing future targeted therapies.

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“…Patients with SCC, who comprise about 40% of all NSCLC cases, are very rarely responsive to targeting agents, and specific genetic alterations in SCC have not been identified to date. Recent molecular analyses have identified genes that may play important roles in lung squamous cell tumorigenesis, including FGFR1 , PIK3CA (phosphoinositide-3-kinase catalytic alpha polypeptide), SOX2 , and DDR2 [ 3 , 22 , 23 ]. Tumor cell lines harboring DDR2 mutations have shown increased sensitivity to multiple tyrosine kinase inhibitors in vitro and in vivo , including small molecule inhibitors such as dasatinib, nilotinib, and AP24534 [ 3 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients

Lee

Jung

et al. 2017

Cancer Res Treat

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PurposeThe discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer.Materials and MethodsWe selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays.ResultsWe identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant–bearing cells.ConclusionOur results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.

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

Cited by 9 publications

References 34 publications

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes

Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients

Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients

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