New Studies Reveal How Cancer Cells Survive Chemotherapy and Resist Treatment

New research published this month in Nature Aging and Nature reveals several biological mechanisms that allow cancer cells to survive chemotherapy and resist treatment, pointing to potential new approaches for combination therapy. The studies identify fructose as a driver of ovarian cancer spread, describe how platinum chemotherapy induces 'zombie cells' that fuel lung and ovarian tumor growth, and show that mitochondrial metabolism determines sensitivity to a key colorectal cancer drug.

One study, from The Wistar Institute and published in Nature Aging, found that cancer cells not killed by chemotherapy send signals to neighboring tumor cells, helping them become more capable of spreading. The researchers identified fructose as a key messenger in this process, revealing a previously unrecognized way that treatment-surviving cancer cells may promote the spread of cancer. In experiments, molecules released by chemotherapy-surviving cells were found to significantly increase the spread of cancer cells in a preclinical model. Fructose was being produced by the surviving cells and sent as the signal for increased spread. Without chemotherapy treatment, consuming the high levels of fructose found in sugary drinks can also signal cancer to spread. Through a CRISPR screen, the team discovered that fructose suppresses cholesterol within neighboring cells; cholesterol is important for cells to stick to each other, so decreased cholesterol allows cells to more easily escape and spread. The finding that fructose lowers cholesterol production has clinical implications, as statins, taken by 39 million people in the United States, lower cholesterol production. The team found that statins alone decreased the glue between cells to promote escape and are now examining whether these medications could be interfering with the effects of chemotherapy, though they stress this isn't a reason for patients to stop taking them. The researchers noted that ovarian cancer is most common in postmenopausal women who are often already on statins. They also believe other cancers that spread within the torso, such as pancreatic, colon, and liver cancers, could behave similarly, and follow-up experiments are planned.

Another study, also published in Nature Aging, investigated how platinum-based chemotherapies such as cisplatin affect tumor behavior in non-small cell lung cancer and high-grade serous ovarian cancer. The researchers found that platinum chemotherapy can push a subset of cancer cells into senescence—a state in which cells remain alive but no longer divide. These so-called 'zombie cells' release TGFβ, a signaling molecule that helps nearby cancer cells survive, grow, and resist treatment. Analysis of patient data showed that tumors displaying features of senescence after platinum treatment were linked to poorer outcomes in both lung and ovarian cancers. The tumor-promoting response was most pronounced with platinum chemotherapy; while drugs such as docetaxel and palbociclib also induced senescence, they did not trigger the same TGFβ-enriched SASP. The study also found that age influenced treatment response, with tumors in middle-aged animals growing more readily than in younger mice. Blocking TGFβ signaling from senescent cells, or removing the cells using senolytic treatment, prevented the tumor-promoting effects of therapy-induced senescence. The findings indicate that combining platinum-based chemotherapy with therapies that target senescent cells or their signaling pathways could represent a promising direction for improving treatment effectiveness.

A third study, published in Nature, examined resistance to 5-fluorouracil (5FU), a cornerstone of colorectal cancer chemotherapy. The researchers demonstrated in a range of colorectal cancer models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitized colorectal cancer cells to 5FU, resulting in delayed tumor growth and prolonged survival in preclinical models. Analysis of patient data suggested that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy, proposing a rational strategy for combination therapy.

The authors of these studies emphasize that further clinical research will be needed before these approaches influence patient care. The findings nonetheless advance understanding of the biological processes behind treatment resistance and identify potential targets for more precise treatment strategies.