Expression and Mutational Status of c-kit in Small-Cell Lung Cancer

Abstract

Purpose: The c-kit protein, also known as CD117, is a member of the type III receptor tyrosine kinase family. Kinase activity has been implicated in the pathophysiology of many tumors, including small-cell lung carcinoma (SCLC). Autocrine or paracrine activation of c-kit by its ligand has been postulated for lung cancer, but this receptor can also be activated by mutations of the c-kit gene. We examined c-kit expression and mutational status in SCLC to verify its putative expression and genetic alterations, as well as its eventual prognostic impact.Experimental Design: We studied 60 SCLC samples to determine the mutations of the coding region of the gene; the exons 9 and 11 were analyzed by PCR-single-strand conformational polymorphism and automated sequencing. Moreover, c-kit expression was evaluated in 55 samples by immunohistochemical method.Results: Expression of c-kit was demonstrated in about 40% of SCLC samples. Two mutations in exon 9 and three mutations in exon 11 were found. Kaplan-Meier analysis revealed no prognostic significance of c-kit expression for survival.Conclusions: In our series, the expression of c-kit and its mutational status failed to appear relevant or to have a significant impact on survival; this makes the therapeutic approach with an inhibitor of tyrosine kinase more difficult in SCLC until a sure demonstration of c-kit implication is obtained for this tumor.

Detection of c‐kit mutational status in small‐cell lung cancer in a Chinese cohort

“…9 At the same time, Boldrini et al tested 60 SCLC samples and explored two mutations in exon 9 and three mutations in exon 11. 4 DNA aberrations in exon 13 or in exon 17 have not been reported previously.…”

“…Our findings are in agreement with previous studies showing that KIT expression was not related to clinical outcomes. 4,7 Further analysis revealed that KIT expression was not associated with any common clinical parameters, including sex, age, performance status, and disease stage, which represent established prognostic factors for survival in SCLC. 4 In our work, disease stage and treatment status had a significant influence on OS.…”

“…KIT protein expression was found in 79-88% of SCLC cell lines and the tyrosine kinase inhibitor imatinib had an inhibitory effect on SCLC cell growth by the inactivation of KIT. [4][5][6] Nevertheless, there was no observed antitumor activity in several phase II clinical trials conducted in SCLC patients, leaving inconclusive results of the effect of imatinib against SCLC with the targeted KIT receptor. 7,8 Several studies have illustrated the mutational status of the c-kit gene in Caucasian cohorts with small case numbers or limited domains, 4,9,10 but no determination of the c-kit mutational status has yet been reported in Chinese patients with SCLC.…”

“…[4][5][6] Nevertheless, there was no observed antitumor activity in several phase II clinical trials conducted in SCLC patients, leaving inconclusive results of the effect of imatinib against SCLC with the targeted KIT receptor. 7,8 Several studies have illustrated the mutational status of the c-kit gene in Caucasian cohorts with small case numbers or limited domains, 4,9,10 but no determination of the c-kit mutational status has yet been reported in Chinese patients with SCLC. To identify the frequency of c-kit mutations in Chinese SCLC patients and further clarify whether or not KIT is a candidate for molecular-targeted therapy, we examined SCLC tumors from Chinese patients in terms of c-kit mutations in a variety of domains, determined KIT expression levels, and correlated c-kit mutation/expression with clinical characteristics.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…Expression of KIT and its ligand, stem cell factor (SCF), are found in 30 to 100% of SCLCs, 87–92 though mutations such as those that drive gastrointestinal stromal tumors are generally not present. Numerous preclinical studies showed that KIT inhibitors, including imatinib, could inhibit both kinase activity and cellular proliferation in SCLC.…”