Tumors need to accumulate genetic changes, so-called mutations, to resist therapies. However, most mutations are harmful and can cause cancer cell death. Head and neck cancers subdue harmful mutations to resist drugs. Predicting how quickly mutations accumulate in tumors is crucial for doctors to decide when and how to treat patients. Unfortunately, this remains challenging, because the mechanisms that allow cancer cells to survive harmful mutations are not well understood. Our research uncovered a new mechanism, called HSP90 capacitance, that promotes mutation accumulation in cancer. Just like an electrical capacitor stores and releases energy, HSP90 capacitance allows seemingly harmless mu...

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Tumors need to accumulate genetic changes, so-called mutations, to resist therapies. However, most mutations are harmful and can cause cancer cell death. Head and neck cancers subdue harmful mutations to resist drugs. Predicting how quickly mutations accumulate in tumors is crucial for doctors to decide when and how to treat patients. Unfortunately, this remains challenging, because the mechanisms that allow cancer cells to survive harmful mutations are not well understood. Our research uncovered a new mechanism, called HSP90 capacitance, that promotes mutation accumulation in cancer. Just like an electrical capacitor stores and releases energy, HSP90 capacitance allows seemingly harmless mutations to later affect how tumor cells respond to stress and resist therapies. We showed that HSP90 capacitance promotes resistance to common drugs used in the clinical treatment of head and neck cancers. HSP90 capacitance is surprising because it is rapid and involves an unexpected but vital biological process: protein folding. Proteins must fold into specific shapes to function; HSP90 is critical in this process and can even mitigate the harmful effects of certain mutations by assisting in the proper folding of the encoded mutant proteins. We showed that by acting this way, the HSP90 capacitor allows cancer cells not only to survive but further enables them to adapt to stressful conditions that would normally eliminate them. Identifying strategies to prevent HSP90 capacitance - how HSP90 allows mutations to accumulate - and delineating the mechanisms that promote it within tumors will have significant implications for personalizing cancer prevention and treatment. This research could transform our understanding of how tumors progress and resist therapies, potentially revealing new strategies to prevent therapy resistance and slow down tumor development in various cancers by targeting HSP90 capacitance.

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