Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells

Area of Science:

• Cancer research
• Pharmacogenomics
• Molecular oncology

Background:

• Approved cancer drugs are often too expensive and offer limited clinical benefits.
• Existing cancer therapies, particularly topoisomerase II poisons, can be improved.
• Treatment-associated transcript levels offer a potential avenue for enhancing drug efficacy.

Purpose of the Study:

• To investigate if transcript levels can optimize the response to topoisomerase II poisons.
• To identify and validate novel druggable targets that enhance etoposide's anti-cancer effects.

Main Methods:

• Analysis of transcriptomes from Acute Myeloid Leukemia (AML) cell lines treated with etoposide.
• Identification of drug targets using network co-regulation and cell survival essentiality criteria.
• Functional validation of identified targets in combination with etoposide.

Main Results:

• Eleven druggable targets influencing etoposide cytotoxicity were identified and confirmed.
• Pre-treatment gene expression predicted etoposide response, with some targets synergizing (e.g., PARP9).
• Etoposide-repressed targets (e.g., PLK1) showed independent cytotoxicity, while others (e.g., mTOR) mimicked etoposide's effects and were cytotoxic alone or in combination.

Conclusions:

• Both baseline gene expression and treatment-induced transcript changes are crucial for etoposide's efficacy.
• Modulating identified targets can enhance etoposide's cancer-killing potential.
• This strategy can guide the development of combination therapies or alternatives for DNA-damaging anticancer drugs.