A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer.

IF 6.8 1区医学 Q1 ONCOLOGY

NPJ Precision Oncology Pub Date : 2025-03-11 DOI:10.1038/s41698-025-00838-4

Gary Middleton, Helen L Robbins, Peter Fletcher, Joshua Savage, Manita Mehmi, Yvonne Summers, Alastair Greystoke, Nicola Steele, Sanjay Popat, Pooja Jain, James Spicer, Judith Cave, Paul Shaw, David Gilligan, Danielle Power, Dean Fennell, Maya Bajracharya, David J McBride, Uma Maheswari, Alexander M Frankell, Charles Swanton, Andrew D Beggs, Lucinda Billingham

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引用次数: 0

Abstract

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).

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目前还没有针对 STK11 缺失型 NSCLC 的分层疗法。STK11缺失会介导mTORC激活、GLUT1上调和糖酵解增加。这种新陈代谢重编程可能代表了一种治疗脆弱性，可通过抑制 mTORC1/2 靶向治疗。在国家肺基质试验的 B2 组中，54 名 NSCLC 患者接受了 vistusertib 治疗，其中 49 人是 STK11 基因缺陷患者（30 人有 KRAS 突变（B2D），19 人没有 KRAS 突变（B2S））。客观应答率（OR）和持久临床获益率（DCB）及95%可信区间（CrI）是通过贝叶斯β-二叉共轭分析生成的后验概率分布估算得出的。在 B2D 中，2 名按方案治疗的患者获得了 OR（估计真实 OR 率（95%CrI）为 9.8% (2.4-24.3)）。真实 DCB 率估计值（95%CrI）：B2D 24.4% (11.1-42.3)，B2S 14.6% (3.6-34.7)。总的来说，在这种情况下不能推荐使用维司他韦。纵向ctDNA分析显示治疗后SMARCA4突变富集。体外研究显示，mTORC1/2抑制可通过AKT再激活产生适应性抗性。(NCT02664935、ISRCTN38344105、EudraCT 2014-000814-73，2015 年 6 月 10 日）。

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来源期刊

NPJ Precision Oncology ONCOLOGY-

CiteScore

9.90

自引率

1.30%

发文量

审稿时长

18 weeks

期刊介绍： Online-only and open access, npj Precision Oncology is an international, peer-reviewed journal dedicated to showcasing cutting-edge scientific research in all facets of precision oncology, spanning from fundamental science to translational applications and clinical medicine.