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Adaptation of Semiautomated Circulating Tumor Cell (CTC) Assays for Clinical and Preclinical Research Applications
Published on: February 28, 2014
Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens
H Burger1, M A den Bakker, G Stoter
1Department of Medical Oncology, Erasmus MC, Josephine Nefkens Building (Room Be420), PO Box 1738, 3000 DR Rotterdam, The Netherlands. h.burger@erasmusmc.nl
Abstract:
Previous studies have shown that STI571, a selective tyrosine kinase inhibitor of c-KIT, is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumours (GIST), especially those that have activating mutations in the c-kit exon 11 that encodes the juxtamembrane (JM) domain of the c-KIT oncoprotein. We examined the prevalence of activating exon 11 c-kit mutations in 26 small-cell lung cancer (SCLC) cases in order to explore whether this disease is also a potential target for treatment with STI571. Expression of c-KIT, estimated by immunohistochemistry, was demonstrated in 14 out of 22 SCLC samples (64%); nine samples showed moderate to strong staining (41%), five samples were weakly positive (23%), whereas eight samples (36%) were negative for CD117. Next, we examined the mutational status of exon 11 of the c-kit gene, by single-stranded conformational polymorphism (SSCP) and sequencing in all of the cKIT/CD117-positive tumours. However, no activating mutations in the c-kit exon 11 were found by either technique. Apparently, c-KIT oncoprotein expression in SCLC was not correlated with activating mutations in c-kit exon 11. In analogy to GISTs, our results could imply that SCLC patients would not benefit from treatment with STI571.
Insights
Small-cell lung cancer (SCLC) expresses c-KIT oncoprotein, but lacks the exon 11 mutations targeted by STI571. Therefore, SCLC patients are unlikely to benefit from this tyrosine kinase inhibitor treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- STI571 is a tyrosine kinase inhibitor effective against c-KIT/CD117-positive gastrointestinal stromal tumors (GIST).
- Efficacy in GIST is linked to activating mutations in the c-kit exon 11, encoding the juxtamembrane domain.
Purpose of the Study:
- To investigate the prevalence of activating c-kit exon 11 mutations in small-cell lung cancer (SCLC).
- To determine if SCLC is a potential target for STI571 treatment.
Main Methods:
- Immunohistochemistry used to assess c-KIT/CD117 expression in 26 SCLC samples.
- Single-stranded conformational polymorphism (SSCP) and sequencing employed to detect mutations in c-kit exon 11 of cKIT/CD117-positive tumors.
Main Results:
- c-KIT/CD117 expression was observed in 64% of SCLC samples (14/22), with moderate to strong staining in 41% (9/22).
- No activating mutations in c-kit exon 11 were detected in any of the cKIT/CD117-positive SCLC samples.
- c-KIT oncoprotein expression in SCLC was not associated with activating c-kit exon 11 mutations.
Conclusions:
- The absence of targetable c-kit exon 11 mutations suggests SCLC may not respond to STI571.
- Results indicate that SCLC patients are unlikely to benefit from STI571 therapy, unlike GIST patients with specific mutations.
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