Resistance Signatures Manifested in Early Drug Response in Cancer and Across Species

Area of Science:

• Oncology
• Genomics
• Evolutionary Biology

Background:

• Therapeutic resistance is a primary driver of cancer treatment failure.
• Non-genetic mechanisms, particularly drug-resistant transcriptional cell states, are increasingly implicated.
• The link between early cellular drug responses and long-term resistance remains unclear.

Purpose of the Study:

• To investigate the connection between early cellular drug response and long-term therapeutic resistance.
• To determine if early resistance-associated transcriptional responses are evolutionarily conserved.
• To identify potential therapeutic targets for overcoming drug resistance.

Main Methods:

• Integrated analysis of long-term drug resistance and early drug response data across cancer cell lines, bacteria, and yeast.
• Utilized CRISPR-Cas9 gene editing to assess the role of resistant state markers.
• Validated findings in human cancer patient trials and premalignant lesion studies.

Main Results:

• Drug-naive and early-treatment cancer cell states share transcriptional properties with fully resistant states.
• These shared transcriptional properties are, in part, evolutionarily conserved across species.
• CRISPR-Cas9 knockout of resistant state markers enhanced sensitivity to Prexasertib in ovarian cancer cells.
• Early resistant state signatures accurately predicted therapy responders versus non-responders in human cancer trials.
• These signatures also distinguished premalignant lesions with high vs. low progression risk.

Conclusions:

• Non-genetic, drug-resistant transcriptional cell states are critical in cancer therapeutic resistance.
• These states are conserved across species and detectable early in treatment.
• Early detection of these states can predict treatment outcomes and disease progression, offering novel therapeutic strategies.