Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to...

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Anaplastic lymphoma kinase (ALK) inhibitors are effective treatments for lung cancer with ALK rearrangements.
• Acquired resistance to ALK inhibitors (ALKi) is a significant clinical challenge, limiting long-term treatment efficacy.

Purpose of the Study:

• To develop a strategy for overcoming ALKi resistance using a meta-analysis of transcriptome data.
• To identify novel therapeutic compounds that can inhibit the growth of ALKi-resistant cancer cells.

Main Methods:

• Performed a meta-analysis of transcriptome data from cell models of acquired ALKi resistance.
• Identified consistent gene expression signatures associated with resistance development.
• Conducted computational drug screening using identified gene signatures.
• Validated candidate compounds in vitro and analyzed their molecular impact via RNA-sequencing.

Main Results:

• Identified specific gene signatures that are consistently altered during the development of ALKi resistance.
• Emetine was identified as a promising compound through computational drug screening.
• Emetine demonstrated effectiveness in inhibiting the growth of ALKi-resistant cancer cells.
• Drug-induced RNA-sequencing provided insights into emetine's mechanism of action on resistant signatures.

Conclusions:

• A transcriptome-guided approach can effectively identify strategies to overcome acquired resistance to ALK inhibitors.
• Emetine represents a potential therapeutic agent for treating ALKi-resistant lung cancer.
• This systematic methodology facilitates efficient drug discovery for overcoming acquired resistance in cancer therapy.