Mebendazole restores gefitinib activity by inducing DNA damage in resistant lung cancer cells

Combining the microtubule-disrupting drug mebendazole with gefitinib suppressed tumor growth in a preclinical model of gefitinib-resistant non-small cell lung cancer, according to the study. The effect was associated with increased DNA damage and replication-associated cellular stress, suggesting that targeting microtubule dynamics may overcome one mechanism of resistance to EGFR-targeted therapy.

The researchers tested the approach in HCC827 GR5 cells, a laboratory model of resistant EGFR-mutant non-small cell lung cancer. Gefitinib alone had little effect on viability at the tested concentration, with cell viability measured at 92.7 ± 1.5%. Mebendazole was more effective on its own: viability fell to 79.7 ± 0.6% at 0.1 micromolar and 29.7 ± 0.6% at 0.5 micromolar, with both changes significant at p < 0.001. The combination of 1 micromolar gefitinib and 0.1 micromolar mebendazole reduced viability further to 37.7 ± 0.6%.

DNA assays connected the cellular effect to genomic injury. An alkaline comet assay detected significantly more single-strand DNA damage after combination treatment, with a reported tail intensity of 22.33 ± 0.56% and p < 0.001. A neutral comet assay also indicated elevated levels of double-strand DNA breaks. In addition, mebendazole activated γ-H2AX in a dose-dependent manner at p < 0.001. Together, these observations support a mechanism in which disruption of microtubule dynamics intensifies replication stress and activates DNA-damage signaling, leaving resistant tumor cells less able to tolerate gefitinib treatment.

In vivo, combined treatment significantly slowed tumor growth. Tumor doubling time increased from 6.2 days in controls to 25 days, while the reported growth delay reached 18.8 days, with p < 0.01. The investigators reported no substantial systemic toxicity during treatment. Because the findings came from cell cultures and an animal model, they do not establish that the combination will be safe or effective in people with gefitinib-resistant non-small cell lung cancer. The results instead identify replication stress as a potentially exploitable vulnerability and provide a preclinical basis for further investigating mebendazole as an adjunct to gefitinib.

Subject of Research: Preclinical repurposing of mebendazole to overcome gefitinib resistance in EGFR-mutant non-small cell lung cancer

Article Title: Dual targeting of EGFR signaling and microtubule dynamics enhances replication-associated cellular stress and suppresses tumor growth in gefitinib-resistant non-small cell lung cancer

Article References: El-Tanani, M., Satyam, S. M., Prabhakar, S., El-Tanani, Y., Safaii, E., Rabbani, S. A., & Sutherland, M. (2026). Dual targeting of EGFR signaling and microtubule dynamics enhances replication-associated cellular stress and suppresses tumor growth in gefitinib-resistant non-small cell lung cancer. PLOS One, 21(10), e0360164. https://doi.org/10.1371/journal.pone.0360164

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360164

Keywords: mebendazole, gefitinib, drug resistance, non-small cell lung cancer, EGFR, microtubule disruption, replication stress, DNA damage, tumor growth, cancer therapeutics, Dual, targeting