Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer

Bashir Lawal; Yu-Cheng Kuo; Alexander Th Wu; Hsu-Shan Huang

Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer

Am J Cancer Res. 2023 Jun 15;13(6):2598-2616. eCollection 2023.

Authors

Bashir Lawal^{1

2}, Yu-Cheng Kuo^{3

4}, Alexander Th Wu^{5

6

7

8}, Hsu-Shan Huang^{8

9

10

11

12}

Affiliations

¹ UPMC Hillman Cancer Center, University of Pittsburgh Pittsburgh, PA 15260, USA.
² Department of Pathology, University of Pittsburgh Pittsburgh, PA 15260, USA.
³ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁴ School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University Taichung 40402, Taiwan.
⁵ The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
⁶ Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University Taipei 11031, Taiwan.
⁷ TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁸ Graduate Institute of Medical Sciences, National Defense Medical Center Taipei 11490, Taiwan.
⁹ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica Taipei 11031, Taiwan.
¹⁰ Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
¹¹ School of Pharmacy, National Defense Medical Center Taipei 11490, Taiwan.
¹² PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University Taipei 11031, Taiwan.

PMID: 37424807
PMCID: PMC10326574

Abstract

Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC₅₀ values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.

Keywords: NLOC-15A; epidermal growth factor receptor (EGFR); non-small-cell lung cancer (NSCLC); small molecule.