Repurposing Lapatinib and Tucatinib as Dual Inhibitors of Bcl-2 and TYMS in Breast Cancer: Insights from Transcriptomic, Computational and Cellular Assays

Abstract

Breast cancer remains a leading cause of cancer related deaths worldwide. HER2-positive subtypes, marked by HER2 receptor over expression often exhibit aggressive behavior. Advances in high-throughput sequencing have revealed new molecular targets, paving the way for more precise therapies. Targeted therapies inhibit HER2 signaling, improving clinical outcomes. However, tumour resistance and survival pathways remain challenges. Identifying alternative targets of HER2 inhibitors may uncover new pathways to suppress tumour growth and improve treatment efficacy. Publicly available RNA-Seq datasets were processed in Galaxy to profile differential gene expression. Bcl-2, an anti-apoptotic regulator and TYMS, a key enzyme in DNA synthesis have emerged as lead candidates. Twenty literatures derived HER2 inhibitors were docked against both proteins, and 100 ns molecular dynamics simulations refined binding stability and validated by functional in-vitro cellular assays. Lapatinib showed the strongest binding to Bcl-2, while tucatinib had the lowest binding energy for TYMS. Both drugs displayed binding profiles resembling their respective controls. Lapatinib and tucatinib are both targeted therapies primarily used to treat HER2-positive cancers. Our study suggests that these agents may also exert effects beyond their primary targets, including potential roles in modulation of Bcl-2 for lapatinib and TYMS inhibition for tucatinib. Furthermore, we observed correlation between Bcl-2 and TYMS expression in breast cancer suggesting that their interplay may influence tumour progression, prognosis, and therapy responsiveness. Our study highlights that lapatinib and tucatinib, beyond HER2 inhibition, may also target Bcl-2 and TYMS respectively. This dual functionality could improve therapeutic strategies against HER2-positive breast cancer. Further biochemical and clinical validation will be necessary to confirm their mechanistic significance.

Graphical Abstract

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