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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Detection of overexpressed and phosphorylated wild-type kit receptor in surgical specimens of small cell lung cancer
Elena Tamborini1, Lorena Bonadiman, Tiziana Negri
1Experimental Molecular Pathology, Department of Pathology, Istituto Nazionale per lo Studio e al Cura dei Tumori, 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.
Insights
New research on small cell lung cancer (SCLC) reveals that wild-type KIT receptors are overexpressed and activated, suggesting a potential target for tyrosine kinase inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Current chemotherapies for advanced small cell lung cancer (SCLC) offer limited survival benefits.
- Novel molecular targets are crucial for developing effective SCLC therapies.
Purpose of the Study:
- To investigate the role of the KIT receptor and its ligand, stem cell factor, in SCLC.
- To identify potential molecular targets for SCLC treatment.
Main Methods:
- Screening of 13 stage I SCLC surgical specimens for c-Kit gene mutations and KIT receptor expression/activation.
- Analysis of KIT receptor and stem cell factor using sequencing, immunoprecipitation, Western blotting, immunocytochemistry, and retrotranscription PCR.
Main Results:
- Wild-type KIT receptors were detected in all SCLC specimens.
- KIT receptors were found to be activated/phosphorylated, with expression levels at least 10 times higher than in normal lung tissue.
- The presence of stem cell factor suggests an autocrine loop driving KIT activation.
Conclusions:
- SCLC exhibits an autocrine loop involving overexpressed and phosphorylated wild-type KIT in the presence of stem cell factor.
- This KIT molecular profile presents a promising therapeutic target for SCLC.
- Targeting wild-type KIT with tyrosine kinase inhibitors may offer a new treatment strategy for SCLC.