# Asiatic Acid from Centella asiatica as a Potent EGFR Tyrosine Kinase Inhibitor with Anticancer Activity in NSCLC Cells Harboring Wild-Type and T790M-Mutated EGFR

## TL;DR

Asiatic acid from Centella asiatica shows strong anticancer activity by inhibiting EGFR in lung cancer cells, including those with a resistant mutation.

## Contribution

Asiatic acid is identified as a novel EGFR tyrosine kinase inhibitor effective against both wild-type and T790M-mutated EGFR.

## Key findings

- Asiatic acid potently inhibits wild-type and double-mutant EGFR with better binding energy than existing drugs.
- Asiatic acid reduces cancer cell viability and induces apoptosis without harming normal lung cells.
- Asiatic acid suppresses ERK and Akt signaling pathways and inhibits EGFR activation in lung cancer cells.

## Abstract

Lung cancer is a leading cause of cancer mortality worldwide. Targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a significant advance in the management of lung cancer. However, their long-term efficacy is often limited by acquired resistance, particularly due to the T790M mutation, highlighting the need for novel EGFR-TKIs. Although compounds derived from Centella asiatica have demonstrated anticancer potential, their role in EGFR inhibition has not yet been reported. In this study, we investigated the inhibitory activity of two primary constituents, asiaticoside and asiatic acid, against wild-type and double-mutant (L858R/T790M) EGFR, as well as the anticancer effects of the more potent compound in lung cancer cells. A kinase activity assay revealed that asiatic acid potently inhibited both wild-type and double-mutant EGFR, whereas asiaticoside showed minimal inhibitory activity. Molecular docking demonstrated that asiatic acid bound to the ATP-binding pocket of both EGFR forms with binding energies superior to those of erlotinib and osimertinib. Treatment with asiatic acid significantly (i) reduced viability of A549 and H1975 cells while remaining non-toxic to BEAS-2B normal lung cells, (ii) enhanced cancer cell apoptosis, (iii) suppressed extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) signaling pathways, and (iv) inhibited EGFR activation in A549 and H1975 cells. These results suggest that asiatic acid is a promising lead compound for anticancer drug development.