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Research Article: Whole-exome sequencing explored mechanism of selpercatinib resistance in RET-rearranged lung adenocarcinoma transformation into small-cell lung cancer: a case report

Date Published: 2023-12-06

Abstract:
Small cell transformation was one mechanism by which EGFR-mutation NSCLC acquired resistance after tyrosine kinase inhibitors (TKIs) treatment. A few reports of small cell transformation occurred in other oncogene-driven lung cancers. We found the first case of transformation of a RET-rearranged lung adenocarcinoma to SCLC after selpercatinib, a novel highly selective RET TKIs. Whole-exome sequencing (WES) was used to explore alteration in gene expression in tumor tissue at initial diagnosis and after transformation into small cell carcinoma. We found that transformed into SCLC tumor tissue had inactivation of RB1 and TP53, with RET fusion was still present. In addition, the APOBEC family of cytidine deaminases appeared amplification. Although RET rearrangement still existed, using another RET TKIs was ineffective, and etoposide plus platinum might be an effective rescue treatment.

Introduction:
Genomic rearrangement of RET occurred in 1–2% of non-small cell lung cancer (NSCLC) and had been confirmed as an oncogenic driver in NSCLC [1]. Two highly selective RET tyrosine kinase inhibitors (TKIs), namely selpercatinib (LOX-292) and pralsetinib (Blue-667), had been approved by the FDA for RET-rearranged NSCLC. LIBRETTO-001 reported the median duration of response was 17.5 months with selpercatinib in RET fusion-positive NSCLC who had previously received platinum-based chemotherapy [2]. The ARROW study…

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