Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

Abstract

Non-small cell lung cancer (NSCLC) is a prominent subtype of lung carcinoma that accounts for the majority of cancer-related deaths globally, and it is responsible for about 80% to 85% of lung cancers. Mitogen-Activated Protein Kinase (MAPK) signaling pathways are a vital aspect of NSCLC, and have aided in the advancement of therapies for this carcinoma. Targeting the Ras/Raf/MEK/ERK pathway is a promising and alternative method in NSCLC treatment, which is highlighted in this review. The introduction of targeted medicines has revolutionized the treatment of patients with this carcinoma. When combined with current systems biology-driven stratagems, repurposing non-cancer drugs into new therapeutic niches presents a cost-effective and efficient technique with enhancing outcomes for discovering novel pharmacological activity. This article highlights the successful cutting-edge techniques while focusing on NSCLC targeted therapies. The ultimate challenge will be integrating these repurposed drugs into the therapeutic regimen of patients affected with NSCLC to potentially increase lung cancer cure rates.

Keywords: MAPK; drug repurposing/repositioning; inhibitors; non-small cell lung cancer; targeted therapy.

Figure 1

A pie chart representing the classification of lung cancer along with the characteristics, origin and histopathology of each type. (The above histopathology pictures were retrieved from https://www.lungevity.org/).

Figure 2

A few symptoms and risk factors causing NSCLC in humans.

Figure 3

A pie of pie chart determining the frequencies of different driver mutations in lung adenocarcinoma.

Figure 4

In NSCLC, oncogenes including EGFR, KRAS, and EML4-ALK are activated, while tumor-suppressor genes including RAR-beta, RASSF1, p16INK4a and p53 are inactivated. In the KEGG MAPK signaling network, the Ras/Raf/MEK/ERK signaling pathway is emphasized (13).

Figure 5

Small molecule inhibitors that are approved and are in clinical trials targeting Ras/Raf/MEK/ERK (MAPK) cascade for the treatment of NSCLC (48, 49).

Figure 6

The process of repurposing a drug for a new indication. Target based drug repurposing: Potent drug candidates targeting NSCLC can be predicted through in silico target-based drug repurposing approach based on several databases, tools and software. Then anticancer properties of predicted drugs can be validated in vitro via several cell-based assays for cancer followed by in vivo animal models. Further validation is done in clinical trials (phases 2 & 3 only) and then the drugs to be repurposed can be approved by FDA for clinical usage on the market.