Middleton Gary, Robbins Helen L, Fletcher Peter, Savage Joshua, Mehmi Manita, Summers Yvonne, Greystoke Alastair, Steele Nicola, Popat Sanjay, Jain Pooja, Spicer James, Cave Judith, Shaw Paul, Gilligan David, Power Danielle, Fennell Dean, Bajracharya Maya, McBride David J, Maheswari Uma, Frankell Alexander M, Swanton Charles, Beggs Andrew D, Billingham Lucinda
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
Department of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK.
NPJ Precis Oncol. 2025 Mar 11;9(1):67. doi: 10.1038/s41698-025-00838-4.
There are no current stratified medicine options for STK11-deficient NSCLC. STK11 loss mediates mTORC activation, GLUT1 up-regulation and increased glycolysis. This metabolic reprogramming might represent a therapeutic vulnerability targetable with mTORC1/2 inhibition. In arm B2 of the National Lung Matrix Trial 54 patients with NSCLC received vistusertib, of which 49 were STK11-deficient (30 with KRAS mutation (B2D), 19 without (B2S)). Objective response (OR) and durable clinical benefit (DCB) rates with 95% credible intervals (CrI) were estimated from posterior probability distributions generated using Bayesian beta-binomial conjugate analysis. In B2D, 2 per-protocol patients obtained OR (estimated true OR rate (95%CrI) 9.8% (2.4-24.3). Estimates of true DCB rate (95%CrI): B2D 24.4% (11.1-42.3), B2S 14.6% (3.6-34.7). Overall, vistusertib cannot be recommended in this context. Longitudinal ctDNA analysis demonstrates enrichment of SMARCA4 mutations post-treatment. In vitro studies show adaptive resistance to mTORC1/2 inhibition via AKT reactivation. (NCT02664935, ISRCTN38344105, EudraCT 2014-000814-73, 10 June 2015).
目前对于STK11缺陷型非小细胞肺癌（NSCLC）尚无分层医学治疗方案。STK11缺失介导mTORC激活、GLUT1上调及糖酵解增加。这种代谢重编程可能是一个可通过抑制mTORC1/2进行靶向治疗的脆弱靶点。在国家肺部基质试验的B2组中，54例NSCLC患者接受了vistusertib治疗，其中49例为STK11缺陷型（30例伴有KRAS突变（B2D），19例无KRAS突变（B2S））。使用贝叶斯β-二项共轭分析生成的后验概率分布估计了客观缓解（OR）率和持久临床获益（DCB）率及其95%可信区间（CrI）。在B2D组中，2例符合方案患者获得了客观缓解（估计真实OR率（95%CrI）为9.8%（2.4 - 24.3））。真实DCB率的估计值（95%CrI）：B2D组为24.4%（11.1 - 42.3），B2S组为14.6%（3.6 - 34.7）。总体而言，在此情况下不推荐使用vistusertib。纵向循环肿瘤DNA（ctDNA）分析显示治疗后SMARCA4突变富集。体外研究表明通过AKT重新激活对mTORC1/2抑制产生适应性耐药。（NCT02664935，ISRCTN38344105，EudraCT 2014 - 000814 - 73，2015年6月10日）
