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Detection of Overexpressed and Phosphorylated Wild-Type Kit Receptor in Surgical Specimens of Small Cell Lung Cancer

¹ Experimental Molecular Pathology, Department of Pathology, ² Department of Experimental Oncology, ³ Department of Medical Oncology, ⁴ Department of Surgery, Istituto Nazionale per lo Studio e al Cura dei Tumori, Milan; and ⁵ Department IFOM: Institute FIRC (Federazione Italiana Ricerca Cancro) for Molecular Oncology, Milan, Italy

Purpose: The combinations of various chemotherapeutic drugs currently used to treat advanced small cell lung cancer (SCLC) led to similarly poor survival outcomes, which is why new molecular biology approaches are needed to design and select targeted therapies.

Experimental Design: Thirteen stage I SCLC surgical specimens were screened for c-Kit gene mutations by sequencing whole cDNA and for KIT receptor expression/activation by immunoprecipitation and Western blotting. Both the paraffin-embedded and frozen materials were analyzed by immunocytochemistry, and the stem cell factor cognate ligand was assessed by retrotranscription PCR.

Results: In all cases, we showed the presence of wild-type KIT receptors by analyzing the entire coding sequence, which together with the detection of the cognate ligand stem cell factor, supports the establishment of an autocrine loop. In addition, the KIT receptor was activated/phosphorylated. The immunoprecipitation/Western blotting data fit the observed immunophenotype. Interestingly, comparison of the level of KIT expression was at least 10 times higher in the tumoral specimens than the normal reference lungs.

Conclusions: The KIT molecular profile derived from the analysis of SCLC surgical specimens shows that wild-type KIT is overexpressed and phosphorylated in the presence of stem cell factor. This finding, which is consistent with pathological KIT activation driven by an autocrine loop, is particularly interesting in the light of the recent development of new tyrosine kinase inhibitory drugs, which are highly effective in blocking wild-type KIT receptors.

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