Colon cancer is known for its complexity and, above all, for its ability to resist conventional treatments, but a study published in the journal Cancer Discovery has identified and validated, at the preclinical level, a novel strategy that could take advantage of the activation of oncogenic pathways to induce cancer cell death.

This study, which has been headed and led by the researcher Rene Bernards from the NKI (Netherlands Cancer Institute) in Amsterdam, has involved the collaboration of researchers from the Catalan Institute of Oncology (ICO), the IDIBELL and the Hospital de Bellvitge.

Inhibiting PP2A protein to trigger cancer cell death

This study focuses on the inhibition of protein phosphatase 2A (PP2A), an enzyme that plays a crucial role in the regulation of multiple cancer-related cell signalling pathways. The research team has found that inhibition of PP2A not only activates multiple oncogenic pathways (hyperactivation), but also triggers ‘stress’ responses in cancer cells.

Through genetic and compound library screenings, they identified that the combined inhibition of PP2A and WEE1, a kinase involved in cell cycle regulation, had a synergistic anti-tumour effect in multiple cancer models, suppressing tumour growth at the preclinical level, both in cell culture and in animal models. Furthermore, it has been observed that cancer cells treated with this therapeutic combination did not develop resistance and lost their capacity to form tumours.

For the researcher of the ProCURE Programme of ICO and IDIBELL, Alberto Villanueva, “this discovery, once validated in clinical trials with patients, may represent an important step towards the development of an effective treatment for patients with colon cancer”, and adds: “this new pharmacological strategy, based on the hyperactivation of oncogenic signalling pathways, which causes great cellular stress, combined with the disruption of cellular response pathways to stress, may also be effective for the treatment of other types of tumours as demonstrated in the work”.

The combined inhibition of PP2A and WEE1 proteins causes a breakdown in DNA replication triggering the onset of premature mitosis followed by “cell death”. As a consequence of this work, a phase I clinical trial (NCT06109883) will start in the Netherlands in a few months to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination in patients with metastatic colorectal cancer.