Science: Why does anti-cancer therapy fail? Scientists reveal evolutionary mechanisms for cancer cells

In the latest issue of science, a team led by Australia's Garvan Institute of Medicine revealed an "evolutionary" mechanism for cancer cells through research into a variety of cancers, including prostate cancer, melanoma, pancreatic cancer and breast cancerThe scientists have come up with a new strategy to reduce cancer cell resistance and make anti-cancer-targeted therapies more effectiveProfessor David Thomas, lead author of the study, said: "We have identified the basic survival strategies that cancer cells use to develop resistance, which provides us with new potential treatment strategiesDrug Resistance Problem When it comes to drug resistance, perhaps what you've heard more often is that bacteria develop resistanceGenetic mutations that some bacteria have acquired in evolution have allowed them to resist almost all commonly used antibiotics, earning the name "superbugs." Sly cancer cells can also develop resistance to targeted therapiesTargeted therapy inhibits the growth of cancer cells by interfering with the molecules needed for tumor growthDespite the advanced nature of targeted therapies, scientists have found that cancer cells accumulate genetic mutations that avoid targeted therapies, causing cancer progression and treatment failuresHow do cancer cells develop resistance to targeted therapies? To find out what's behind this, in this study, the scientists first analyzed biopsy samples from patients with a variety of different cancers to compare the differences between and after cancer cells received targeted therapyThrough genome-wide sequencing and other methods, they were surprised to find that cancer cells in some ways actually behave like bacteria! Specifically, the genomes of cancer cells that undergo targeted treatment show faster evolution"Our experiments show that cancer cells exposed to targeted therapies produce random genetic mutations faster, much faster than cancer cells that are not exposed to anticancer drugs, a process known as stress mutagenesisLead author Dr Cipponi said: "Ancient single-celled organisms, such as bacteria, also use stress mutagenic processes to evolve when stressed in the environmentNext, researchers conducted a large-scale screening of cancer cells across the genome to find genes associated with the production of drug resistanceThey found that the mTOR signaling pathway was closely related to stress mutagenesis in cancer cellsIn the past, this signaling pathway has been involved in cell growth, inhibiting mTOR allows cells to slow down growthBut the researchers found that the mTOR signaling pathway also accelerates the evolution of cancer cells under pressure from targeted therapies to inhibit the growth of cancer cells by allowing them to "make more mistakes." Dr Cipponi explained: "We found that in anti-cancer treatment, the mTOR signaling pathway allowed genes in cancer cells involved in DNA repair and DNA replication to alter expression, such as from high-fidelity polymerase (copy DNA) to error-prone polymerase, resulting in more genetic mutationsGenomic instability is harmful to cells, but cancer cells seem to be very good at balancing, and the shift to "low-fidelity" repair and replication is only temporaryOnce the drug-resistant genes are developed, these cells switch back to the high-fidelity replication pathway and move into the second phase to ensure that resistant cells continue to survive! New approach to cancer treatment Since cancer cells can adapt to anticancer therapy by increasing DNA replication errors, can this process improve anti-cancer therapies? The researchers hypothesicthat that combining conventional cancer-targeted therapies with drugs against DNA repair mechanisms may make treatment strategies more effective This concept was quickly validated in animal experiments The researchers tested a combination of drugs in a mouse model of pancreatic cancer They teamed up with the cancer drug palbociclib, a drug that selectively targets DNA to repair damaged cells The results showed that the combination of drugs achieved better results than pabosini alone: tumorgrowth was reduced by nearly 60% in 30 days, and the total survival of mice was longer Looking at these positive results, Professor Thomas concluded: "Our findings open up potential new strategies to prevent stress mutagenic changes in cancer, or to make previously resistant treatments more effective." "It is expected that the effectiveness of this new strategy will be validated clinically, allowing more patients to benefit from targeted therapies."