RET 融合作为非小细胞肺癌患者的主要致癌驱动因素和 EGFR 酪氨酸激酶抑制剂的获得性继发耐药。
RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer.
机构信息
Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361013, Fujian, China.
Department of Thoracic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China.
出版信息
J Transl Med. 2022 Sep 4;20(1):390. doi: 10.1186/s12967-022-03593-3.
BACKGROUND
RET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor (EGFR) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood.
METHODS
Targeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary RET fusions and 71 EGFR-mutated NSCLC patients who acquired RET fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs).
RESULTS
Primary RET fusions were more likely associated with females and younger age, with KIF5B being the predominant fusion partner. In baseline patients, both SMAD4 (5.3% vs. 0.0%, P = 0.044) and MYC copy-number gain variants (6.9% vs. 0.0%, P = 0.009) were more frequently co-mutated with KIF5B-RET than CCDC6-RET. By contrast, CDKN2A (11.3% vs. 2.4%, P = 0.003) mutations were significantly enriched in CCDC6-RET-rearranged baseline patients. A significant increase in the proportion of CCDC6-RET was observed in acquired RET-rearranged patients (47.3% vs. 22.5%, P < 0.001). The median progression-free survival (PFS) of patients harboring RB1 and TP53 double-mutations (5.5 vs. 10.0 months, P = 0.020) or ERBB2 amplification (5.6 vs. 10.0 months, P = 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that RET fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs.
CONCLUSIONS
In conclusion, we depicted the mutational profiles of NSCLC patients who harbor RET fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that RET fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC.
背景
RET 融合是 NSCLC 中罕见的致癌驱动因素。虽然在对 EGFR 抑制剂产生耐药性的 NSCLC 患者中发现了激活的 RET 重排，但同时存在的基因组改变的程度以及它们如何影响预后或治疗反应尚不清楚。
方法
使用靶向下一代测序（NGS）评估了 380 名患有原发性 RET 融合的患者和 71 名在对 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）产生耐药后获得 RET 融合的 EGFR 突变型 NSCLC 患者的基线情况。
结果
原发性 RET 融合更可能与女性和年轻患者相关，其中 KIF5B 是主要的融合伙伴。在基线患者中，SMAD4（5.3%比 0.0%，P=0.044）和 MYC 拷贝数增益变异（6.9%比 0.0%，P=0.009）与 KIF5B-RET 的共突变频率均高于 CCDC6-RET。相比之下，在 CCDC6-RET 重排的基线患者中，CDKN2A（11.3%比 2.4%，P=0.003）突变明显富集。在获得性 RET 重排患者中，CCDC6-RET 的比例显著增加（47.3%比 22.5%，P<0.001）。携带 RB1 和 TP53 双突变（5.5 个月比 10.0 个月，P=0.020）或 ERBB2 扩增（5.6 个月比 10.0 个月，P=0.041）的患者中位无进展生存期（PFS）显著短于野生型患者。此外，我们发现 RET 融合与第三代 EGFR-TKIs 的获得性耐药（AR）比前几代 EGFR-TKIs 更相关。
结论
总之，我们描述了基线时或对 EGFR-TKIs 耐药后携带 RET 融合的 NSCLC 患者的突变谱。此外，我们的结果表明，RET 融合介导了第三代 EGFR-TKIs 的继发性耐药，并且可能与 NSCLC 患者的不良预后相关。
Zotero 插件