Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of survival and reduction of disease‐related adverse events is the main goal for oncologists. In this scenario, we present preclinical evidence supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Nonsmall cell lung adenocarcinomas (NSCLC) and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first‐in‐human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induces AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy markedly increases the therapeutic effect of chemotherapy without increasing toxicity. We further show that combination of ABTL0812 and chemotherapy induces nonapoptotic cell death mediated by TRIB3 activation and autophagy induction. We also present preliminary clinical data indicating that TRIB3 could serve as a potential novel pharmacodynamic biomarker to monitor ABTL0812 activity administered alone or in combination with chemotherapy in squamous NSCLC patients. The safety profile of ABTL0812 and its good synergy with chemotherapy potentiate the therapeutic potential of current lines of treatment based on chemotherapy regimens, arising as a promising option for improving these patients therapeutic expectancy.

中文翻译：

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新型的自噬抗癌药ABTL0812增强了腺癌和鳞状非小细胞肺癌的化疗。

大约40％的新诊断肺癌患者是IV期，肿瘤学家的主要目标是提高生存率和减少与疾病相关的不良事件。在这种情况下，我们目前提供的临床前证据支持将ABTL0812与化学疗法联合用于治疗晚期和转移性非小细胞肺腺癌（NSCLC）和鳞状癌。ABTL0812是一种新的化学实体，在成功完成首次在人中试验后显示出优良的安全性和体征后，目前正在进行晚期鳞状非小细胞肺癌与紫杉醇和卡铂（P / C）组合的1b / 2a期临床试验。功效。我们在这里显示，ABTL0812通过诱导TRIB3的过表达和激活肺鳞癌细胞系中的自噬来抑制Akt / mTOR轴。此外，用ABTL0812处理也会诱导AMPK激活和ROS积累。而且，ABTL0812与化学疗法的组合显着增加了化学疗法的治疗效果，而没有增加毒性。我们进一步表明，ABTL0812和化学疗法的结合可诱导由TRIB3激活和自噬诱导的非凋亡细胞死亡。我们还提供了初步的临床数据，表明TRIB3可以作为潜在的新型药效生物标志物，以监测鳞状NSCLC患者单独或与化疗联合使用时ABTL0812的活性。ABTL0812的安全性及其与化疗的良好协同作用增强了基于化疗方案的当前治疗方案的治疗潜力，是改善这些患者治疗预期的有前途的选择。