The activity of a PI3K δ-sparing inhibitor, MEN1611, in non-small cell lung cancer cells with constitutive activation of the PI3K/AKT/mTOR pathway.

Background

Lung cancer remains the leading cause of cancer-related death worldwide. Targeted therapies with tyrosine kinase inhibitors (TKIs) result in improvement in survival for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). Unfortunately, most patients who initially respond to EGFR-TKI ultimately develop resistance to therapy, resulting in cancer progression and relapse. Combination therapy is today a common strategy for the treatment of tumors to increase the success rate, improve the outcome and survival of patients, and avoid the selection of resistant cancer cells through the activation of compensatory pathways. In NSCLC, the phosphoinositide-3-kinase/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been heavily implicated in both tumorigenesis and the progression of disease.

Objectives

In this study, we investigated the efficacy of a PI3K δ-sparing inhibitor, MEN1611, in models of NSCLC sensitive and resistant to EGFR inhibitors (erlotinib and gefitinib) with a wild-type

Methods

We performed functional, biochemical, and immunohistochemistry studies.

Results

We demonstrated good efficacy of MEN1611 in NSCLC devoid of

Conclusions

Overall, this preclinical study indicates that the inhibitor could be a candidate for the treatment of NSCLC with an erlotinib/gefitinib-resistant phenotype and constitutive activation of the PI3K/AKT pathway, a phenotype mimicked by our model system.

Informations de copyright

Copyright © 2023 Papoff, Presutti, Fustaino, Parente, Calandriello, Alemà, Scavizzi, Raspa, Merlino, Salerno, Bigioni, Binaschi and Ruberti.

Déclaration de conflit d'intérêts

Authors GM, MS, MaB, and MoB were employed by the company Menarini Ricerche S.p.A. CNR-IBBC and Menarini Ricerche have been partially supported by the project PISTA PI3K for Solid Tumor therApy a non-refundable grant by Regione Lazio Lazio Innova under the EU program POR FESR 2014-2020 grant n. A0112-2016-13408 and encompasses the activities mentioned in this paper, including personnel costs and laboratory expenses, whose goal has been to study the anticancer effect of the molecule MEN1611. The Menarini Group is the exclusive license owner of MEN1611. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.