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Anaplastic lymphoma kinase expression in small-cell lung cancer
Chiaki Kondoh1,2, Yoshitsugu Horio3, Yuko Hayashi4
1Department of Pathology and Molecular Diagnostics, Aichi Cancer Centre, Nagoya, Japan.
Aims:
Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs.
Methods And Results:
We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib.
Conclusions:
Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript.
Insights
Anaplastic lymphoma kinase (ALK) expression in treatment-naive small-cell lung cancer (SCLC) is intrinsic and not a reliable biomarker for ALK inhibitor therapy. ALK immunohistochemistry is not predictive in this setting.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) immunohistochemistry is crucial for ALK-targeted therapy in lung cancer.
- Small-cell lung cancer (SCLC) transformation is a known resistance mechanism to ALK inhibitors.
- Comprehensive data on ALK expression in treatment-naive SCLC is limited.
Purpose of the Study:
- To investigate ALK expression in treatment-naive SCLC.
- To elucidate the underlying mechanisms of ALK expression in SCLC.
- To assess the potential of ALK expression as a predictive biomarker in SCLC.
Main Methods:
- Examined ALK expression via immunohistochemistry in 142 SCLC tumors.
- Analyzed ALK gene rearrangement, copy number changes, and point mutations.
- Tested crizotinib efficacy on an ALK-expressing SCLC cell line (SKLC2) in vitro.
Main Results:
- ALK was expressed in 11.3% (16/142) of SCLCs, with focal and less intense staining compared to adenocarcinoma.
- No known genetic alterations (rearrangement, amplification, mutations) correlated with ALK expression.
- Crizotinib did not inhibit the SKLC2 SCLC cell line at achievable concentrations.
Conclusions:
- ALK immunohistochemistry is not a predictive biomarker for ALK inhibitor therapy in treatment-naive SCLC.
- Observed ALK expression in SCLC is likely due to intrinsic expression of the normal ALK transcript.
- Current ALK testing methods may not be suitable for predicting response in SCLC.
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