Flavonoids are plant bioactive compounds of great interest in nutrition and pharmacology, due to their remarkable properties as antioxidant, anti-inflammatory, antibacterial, antifungal and antitumor drugs. More than 5000 different flavonoids exist in nature, with a huge structural diversity and a plethora of interesting pharmacological properties. In this work, five flavonoids were tested for their potential use as antitumor drugs against three CRC cell lines (HCT116, HT-29 and T84). These cell lines represent three different stages of this tumor, one of which is metastatic. Xanthohumol showed the best antitumor activity on the three cancer cell lines, even better than that of the clinical drug 5-fluorouracil (5-FU), although no synergistic effect was observed in the combination therapy with this drug. On the other hand, apigenin and luteolin displayed slightly lower antitumor activities on these cancer cell lines but showed a synergistic effect in combination with 5-FU in the case of HTC116, which is of potential clinical interest. Furthermore, a literature review highlighted that these flavonoids show very interesting palliative effects on clinical symptoms such as diarrhea, mucositis, neuropathic pain and others often associated with the chemotherapy treatment of CRC. Flavonoids could provide a double effect for the combination treatment, potentiating the antitumor effect of 5-FU, and simultaneously, preventing important side effects of 5-FU chemotherapy.

About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.