Science: a new mechanism of multidrug resistance in cancer cells

February 20, 2020 / bioun / -- researchers from the Korean Academy of science and Technology (KAIST) have determined the mechanism of transfer of acquired resistance to first-line chemotherapy to second-line targeted treatment, which leads to the "domino effect" of cancer resistance Their study, published in science advanced recently, proposes a new strategy for improving the second-line treatment of cancer in patients with resistance to anticancer drugs Drug resistance to cancer drugs is usually controlled by chemotherapy and targeted therapy Unlike chemotherapy, which inhibits rapid proliferation of cells, targeted therapy blocks a single carcinogenic pathway that blocks tumor growth In many cases, targeted therapy is used as a maintenance therapy or as a second-line therapy after first-line chemotherapy Photo source: KAIST a team of researchers led by yoosik Kim, professor from KAIST Department of chemical and Biomolecular Engineering and KAIST Institute of Health Science and technology, found an unexpected drug resistance feature between chemotherapy and targeted treatment The team further identified a comprehensive mechanism to promote this sequential treatment of drug resistance Mark Borris D aldonza, the lead author of the paper, said: "there are a number of clinical cases that show that targeted treatment is often the least successful in patients who have exhausted all standard treatments These explanations ignite our hypothesis that failure to respond to some chemotherapy may accelerate the evolution of resistance to other drugs, especially those with specific targets "Aldonza and his colleagues extracted a large amount of drug resistance information from the open source database" cancer drug sensitivity genomics "(gdsc), which contains thousands of drug response data entries from various human cancer cell lines Their big data analysis shows that anti mitotic drugs (AMDS), which inhibit excessive cell division, are resistant to cancer cell lines, and also resistant to a targeted treatment called epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) Of all cancer types analyzed, more than 84% of anti amd (representing "paclitaxel") cancer cells were also resistant to at least 9 EGFR-TKIs In lung cancer, pancreatic cancer and breast cancer, paclitaxel is often used as a first-line standard treatment More than 92% of patients show resistance to EGFR-TKIs Professor Kim said: "it's amazing that this indirect resistance can occur between two drugs with different chemical properties "In order to find out how the failure response to paclitaxel resulted in resistance to EGFR-TKIs, the team validated the common drug resistance characteristics they found in the database by generating and analyzing a group of paclitaxel resistant cancer models called" persistent " The results showed that paclitaxel resistant cancer first became more like stem cells, and evolved the ability of self-renewal to adapt to greater stress conditions, such as drug exposure, so as to reshape its stress response What's more surprising is that when researchers studied the metabolic state of cells, EGFR-TKI resistant cells from paclitaxel resistant cancer cells showed a high dependence on energy production processes, such as glycolysis and glutamine decomposition "We found that without energy stimulation such as glucose, these cells would grow older, which is a feature of cells stopping dividing However, this aging is controlled by stem cell factors, which are the factors that taxol resistant cancer cells use to get out of this stagnation and grow again, "said aldonza Professor Kim explained: "before this study, there was no reason to expect that the cascade of changes in cell status that would significantly affect metabolism and cell death from obtaining a cancer stem cell phenotype was related to drug-specific sequential resistance between the two types of treatment "He added:" our work will expand to other models of drug resistance work in more clinically relevant settings (perhaps in clinical trials), which will become increasingly important as sequential treatment strategies will continue to apply to all forms of cancer treatment options "Reference: yoosik Kim et al Prior acquired resistance to paclitaxel relays diverse EGFR targeted therapy persistence mechanisms science advances 07 Feb 2020: Vol 6, No 6, eaav7416 doi: 10.1126/sciadv.aav7416