The novel proautophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous nonsmall cell lung cancer.
Anna López-PlanaPatricia Fernández-NogueiraPau Muñoz-GuardiolaSònia Solé-SánchezElisabet Megías-RodaHéctor Pérez-MontoyoPatricia JaureguiMarc Yeste-VelascoMariana Gómez-FerreriaTatiana ErazoElisabet AmetllerLeire Recalde-PercazNúria Moragas-GarciaAleix Noguera-CastellsMario MancinoTeresa MoránErnest NadalJosé AlfónCarles DomènechPere GasconJose M LizcanoGemma FusterPaloma BragadoPublished in: International journal of cancer (2020)
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.
Keyphrases
- locally advanced
- newly diagnosed
- cell death
- high grade
- small cell lung cancer
- clinical trial
- end stage renal disease
- signaling pathway
- squamous cell carcinoma
- low grade
- oxidative stress
- chemotherapy induced
- cell proliferation
- ejection fraction
- chronic kidney disease
- randomized controlled trial
- machine learning
- phase ii study
- prognostic factors
- single cell
- radiation therapy
- endothelial cells
- cell therapy
- epidermal growth factor receptor
- phase ii
- study protocol
- mesenchymal stem cells
- deep learning
- climate change
- combination therapy
- open label
- protein kinase