Talzenna and Lonsurf for Cancers with TP53 Mutations

 "A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers" by Alruwaili et al., 2024, studied a novel therapeutic approach for colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) by targeting p53-deficient tumors. These cancers often resist conventional therapies and challenging treatment, especially in p53-mutant (p53Mut) variants.

The study highlights a two-drug combination strategy involving trifluorothymidine (TFT), a thymidine analog, and a poly(ADP-ribose) polymerase inhibitor (PARPi). The research demonstrates that TFT induces DNA breaks in p53Mut cancer cells by disrupting post-replicative DNA repair, which is already impaired in these tumors due to the loss of p53. The key insight is that the dysfunction in the base excision repair (BER) pathway, responsible for removing thymidine analogs, allows DNA damage buildup. When a PARP inhibitor is added, it further enhances this damage by inhibiting single-strand break repair, leading to the accumulation of double-strand breaks (DSBs) and cell death.

A significant finding is that this combination selectively targets p53Mut cells, as p53 wild-type cells can activate the p53-p21 axis, which allows them to arrest the cell cycle in the G1 phase and repair DNA damage. In contrast, p53-deficient cells fail to activate this checkpoint, leading to excessive DNA damage and accumulation in the G2 phase, eventually resulting in cell death.

The study demonstrates that the combination of TAS102 (a thymidine analog) and PARP inhibitors (PARPi) significantly enhances tumor reduction in preclinical models of p53-deficient colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). In xenograft models of CRC (HT29 model) and PDAC (MiaPaca2 model), the combination therapy markedly reduced tumor growth compared to monotherapy with either TAS102 or PARPi alone.

For instance, in the PDAC PDX-14312-4p model, the TAS102-PARPi combination extended survival by 27 days (from 70 days with TAS102 alone to 97 days with the combination). Additionally, histological analysis showed reduced proliferation, as indicated by a lower Ki67 index, and increased DNA damage markers, such as γH2AX, in tumors treated with combination therapy.

References

Alruwaili, Mohammed & Naranjo, Maricris & Serio, Hannah & Melendy, Thomas & Straubinger, Robert & Gillard, Bryan & Foster, Barbara & Rajan, Priyanka & Attwood, Kris & Chatley, Sarah & Iyer, Renuka & Fountzilas, Christos & Bakin, Andrei. (2024). A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers. Cell Reports Medicine. 5. 101434. 10.1016/j.xcrm.2024.101434.