Cancer Hospital of China Medical University, Shenyang, China.
Liaoning Cancer Hospital & Institute, Shenyang, China.
Cancer Med. 2022 Nov;11(22):4122-4133. doi: 10.1002/cam4.4764. Epub 2022 May 8.
Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non-small-cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population.
A total of 17,978 Chinese patients with NSCLC who underwent next -generation sequencing (NGS) testing were retrospectively reviewed.
We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active-site mutations, including IDH1 , IDH1 , IDH2 , and IDH2 , were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active-site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p < 0.001) or BRAF (p. V600E, 6.5% vs. 1.0%, p < 0.001), but significantly lower coalterations in activating EGFR (e18-e20, 22.7 vs. 37.9%, p < 0.001) than IDH wild-type patients. Furthermore, we found that active-site IDH mutations were correlated with a short PFS (2-5.6 months) and short OS (2-9.5 months), which may arise as a resistance mechanism against common targeted drugs. In vitro, we experimentally observed that the combination of an IDH inhibitor and EGFR TKI could better inhibit lung cancer cell proliferation than an EGFR TKI alone.
Taken together, this study reveals the molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and provides a theoretical basis for IDH-directed treatment. The potential of IDH mutations as response markers for targeted therapy warrants further investigation.
异柠檬酸脱氢酶（IDH）是癌症治疗的一个有吸引力的靶点，IDH（IDH1/2）抑制剂已被批准用于急性髓系白血病（AML）和胆管癌的靶向治疗。IDH 抑制剂在非小细胞肺癌（NSCLC）患者中的治疗潜力正在积极的临床研究中。因此，研究 NSCLC 患者 IDH 突变的分子和临床特征是必要且有意义的，特别是在中国人群中。
回顾性分析了 17978 例接受下一代测序（NGS）检测的中国 NSCLC 患者，共发现 361 例（2.01%）患者存在 161 种独特的 IDH 突变。常见的活性位点突变，包括 IDH1、IDH1、IDH2 和 IDH2，在 154 例患者（0.86%）中检测到，与男性（p=0.004）和年龄较大（p=0.02）相关。在 NSCLC 中观察到的 IDH 突变谱与胶质瘤或 AML 中的突变谱有很大不同。IDH 活性位点突变的患者中 KRAS（p.G12/13/61）或 BRAF（p.V600E）的共突变显著更高（22.1%比 8.2%，p<0.001；6.5%比 1.0%，p<0.001），但激活 EGFR（e18-e20）的共突变显著更低（22.7%比 37.9%，p<0.001）。此外，我们发现活性位点 IDH 突变与较短的 PFS（2-5.6 个月）和 OS（2-9.5 个月）相关，这可能是对常见靶向药物产生耐药的机制。在体外，我们实验观察到 IDH 抑制剂与 EGFR TKI 的联合应用比单独使用 EGFR TKI 能更好地抑制肺癌细胞的增殖。
综上所述，本研究揭示了中国 NSCLC 患者 IDH 突变的分子和临床特征，为 IDH 靶向治疗提供了理论依据。IDH 突变作为靶向治疗反应标志物的潜力值得进一步研究。
