A novel mutation panel for predicting etoposide resistance in small-cell lung cancer

Abstract

Purpose

Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small-cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC.

Methods

The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). The data regarding sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide.

Results

ROC analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve =0.804 (95% confidence interval: 0.679–0.930,P<0.001).

Conclusion

This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.

Keywords:

• small-cell lung carcinoma
• etoposide
• EP regimens
• IP regimens
• gene mutation

Acknowledgments

Work cited in this review was supported by the National Natural Science Foundation of China (grant numbers 81672267, 81772457, and 81871859) and the Province Natural Science Foundation of Guangdong (grant numbers 2016A030313632 and 2017A030313567).

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

Table S1 Etoposide IC50 values of 54 SCLC cell lines

Table S2 ROC curve of all genes (mutation frequency >10%)