Cancer drug resistance is usually controlled through chemotherapy and targeted therapy. Unlike chemotherapy that inhibits cell proliferation, targeted therapy blocks a single, consistent pathway of tumor growth. Therefore, in many cases, targeted therapy is used as a maintenance treatment or as a second-line after adequate failure of patients to first-line chemotherapy.
A team of researchers led by Professor Yoosik Kim from the Department of Chemistry and Biomolecular Engineering and the Institute of Health Technology of KAIST has discovered an unexpected feature of resistance that occurs between chemotherapy and targeted therapy. The team further identified a comprehensive set of mechanisms of this drug-resistance persister state.
First author Mark Borris D. Aldonza said: "Many clinical cases show that targeted therapy is often the least successful in patients who have exhausted all standard treatments. These explanations confirm our hypothesis that failure to respond to certain chemotherapy may accelerate the evolution of resistance to other drugs, especially those with specific targets."
Aldonza and his colleagues extracted extensive resistance information from the Genomics of Drug Sensitive in Cancer (GDSC), a publicly available dataset containing thousands of drug response data from various human cancer cell lines. Analysis of these data shows that cancer cell lines that are resistant to microtubule-targeting chemotherapy agents display resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs).
Of all cancer types analyzed, more than 84% of cancer cells that were resistant to anti-mitotic drugs convey secondary resistance to at least 9 EGFR-TKIs. Professor Kim said: "Surprisingly, this indirect resistance can occur between two drugs with different chemical properties."
To experimentally explore the co-resistance between paclitaxel (anti-mitotic drug) and EGFR-TKIs, the researchers validated what they found in the database by generating and analyzing a set of paclitaxel-resistant cancer models called " persisters". The results show that paclitaxel-resistant cancers reshape their stress response by enriching stemness, evolving their ability to self-renew to adapt to greater stressful conditions, such as drug exposure. What is even more surprising is that when researchers study the metabolic state of cells, EGFR-TKI persistently resistant cells from paclitaxel-resistant cancer cells show a high dependence on energy production processes such as glycolysis and glutamine breakdown.
"We found that without energy stimulation like glucose, these cells become senescent, which is a feature of cells that stop dividing. However, this aging is controlled by stemness-associated senescence, which is an adaptive stress response mechanism for paclitaxel-resistant cancer cells to get rid of the stagnant state and grow again, "Aldonza said.
Professor Kim explained: "Our work will expand to other working models of drug resistance in a more clinically relevant setting (perhaps in clinical trials), which will become increasingly important as sequential treatment strategies will continue to apply to all forms of anti-cancer treatment options."