Brigatinib and Fructose: New Strategies to Overcome Ovarian Cancer Recurrence

Two preclinical studies published in Nature Aging and Science Advances have uncovered distinct mechanisms driving treatment resistance and metastasis in high-grade serous ovarian cancer (HGSOC), suggesting new therapeutic and dietary interventions. One study reveals that cancer cells surviving chemotherapy use fructose as a signaling molecule to promote metastasis, while the other demonstrates that the lung cancer drug brigatinib can block an early adaptive survival response to PARP inhibitors, enhancing their efficacy.

HGSOC is the most common and lethal gynecologic cancer, with a five-year survival rate of only 30%. Although most patients initially respond to platinum-based chemotherapy, recurrence occurs within three years and accounts for about 90% of deaths. PARP inhibitors, effective in tumors with homologous recombination deficiencies such as BRCA mutations, improve progression-free survival but resistance often develops.

Research from the Mayo Clinic, published in Science Advances, shows that ovarian cancer cells quickly activate a pro-survival program upon treatment with PARP inhibitors. The transcription factor FRA1 is upregulated early and drives expression of genes that promote survival and adaptation. The study found that brigatinib, an ALK inhibitor approved for lung cancer, acts through an ALK-independent pathway to induce dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases. This suppresses Akt and ERK signaling, disrupting the phosphorylation required for FRA1 protein stability. Simultaneous inhibition of both FAK and EPHA2 was essential; inhibiting either alone was insufficient to sensitize HGSOC cells to PARP inhibitors. The effect occurred at brigatinib concentrations below those achieved in the clinic and was independent of HR status, meaning it could address both HR-deficient and HR-proficient tumors.

In multiple patient-derived xenograft mouse models, the combination of brigatinib and a PARP inhibitor induced tumor regression and improved overall survival compared with PARP inhibition alone. A subset of HGSOCs overexpresses both FAK and EPHA2, a co-overexpression associated with worse survival, and tumors that responded robustly to the combination had higher levels of these markers. If further validated, tumors could potentially be tested for these signaling markers, allowing patients with high pathway activity to receive upfront combination therapy rather than waiting for resistance to emerge. The researchers acknowledged the preclinical nature of the study and noted that not all PARP inhibitor–resistant models showed upregulation of FAK or EPHA2, indicating this may not be a universal resistance mechanism.

Separately, scientists at the Wistar Institute demonstrated that cancer cells surviving chemotherapy may promote metastasis by using fructose as a key signaling molecule. Published in Nature Aging, the study focused on HGSOC. Senescent cancer cells that have not been killed by chemotherapy release a cocktail of signaling molecules sufficient to make surviving cancer cells detach from each other and metastasize. This is the first time the effect of these released molecules—rather than the cells themselves—has been shown in a preclinical model. Fructose was found to be abundant in this signaling cocktail, and fructose alone could promote the detachment of cultured cancer cells.

In mice, a high-fructose diet increased metastasis, and an analysis of patient data revealed that elevated fructose levels were associated with more advanced stages of HGSOC at diagnosis. Further experiments showed that fructose signals led cancer cells to decrease cholesterol in their cell membranes, making the cells less sticky and more easily detached to initiate metastasis. The findings raise questions about dietary interventions and the use of statins in cancer patients, though the effect has not yet been tested in humans. The researchers believe the effect may not be limited to ovarian cancer and could extend to other cancers that spread within the torso, such as pancreatic, colon, and liver cancers.

Both studies are preliminary and require further validation in advanced preclinical models and clinical trials before they can be translated to patient care.