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New ruthenium-cyclopentadienyl complexes target specifically mutated KRAS in colorectal cancer
1, 2, 3 , 3, 4 , 4, 5 , 4, 5, 6 , * 1, 2 , * 3
1  CBMA – Centre of Molecular and Environmental Biology, University of Minho, Braga, Portugal
2  IBS-Institute of Science and Innovation for Bio-Sustainability, University of Minho, Braga, Portugal
3  CQE – Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal
4  I3S - Institute for Research and Innovation in Health, Universidade do Porto, Porto, Portugal
5  IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
6  ICBAS - Institute of Biomedical Sciences of Abel Salazar, Universidade do Porto, Porto, Portugal
Academic Editor: Maria Emília Sousa (registering DOI)

Colorectal cancer (CRC) is an important cause of global morbidity and mortality. CRC harboring KRAS mutations accounts for 40% of all CRCs and is resistant to available EGFR inhibitors. Specific targeting of KRAS hotspot mutations is very difficult to achieve, highlighting the need of developing new specific target drugs. In this work, we aimed to evaluate the in vitro anticancer effects and explore the preclinical in vivo “proof of concept” for KRAS-mutated CRC therapy of a new family of ruthenium-cyclopentadienyl complexes.

CRC-derived cell lines with KRAS wild-type and different hotspot mutations were used to determine the phenotypic alterations induced by the complexes. A xenografted CRC mice model was used to determine in vivo toxicity and anti-tumor growth effect.

Our results revealed that Ru complexes are more cytotoxic for CRC cells, decreasing proliferation and inducing apoptosis. Studies with the PMC79 compound showed a decrease in the expression levels of KRAS, ERK and AKT proteins only in CRC-derived cells with KRAS mutation. In the in vivo therapeutical study, tumors treated with PMC79 had a much higher level of necrosis. Furthermore, the expression levels of KRAS, ERK and AKT proteins were also decreased in this model.

Overall, PMC79 has a noticeable effect inhibiting KRAS on CRC cells harboring KRAS mutation and not on CRC cells with KRAS wild type. This new Ru agent is a promising new drug for CRC therapy, suggesting to be a specific and a potential “magic bullet” for CRCs harboring mutated KRAS.

Keywords: Colorectal cancer; KRAS; ruthenium-cyclopentadienyl complexes