Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

© 2021 The Author(s).New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients’ outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.This study has been funded by Instituto de Salud Carlos III (ISCIII) -Fondos FEDER proyects PI16/01468 and PI19/01231

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

Rigosertib (ON-01910.Na) is a small-molecule member of the novel synthetic benzyl-styryl-sulfonate family. It is currently in phase III clinical trials for several myelodysplastic syndromes and leukemias and is therefore close to clinical translation. The clinical progress of rigosertib has been hampered by a lack of understanding of its mechanism of action, as it is currently considered a multi-target inhibitor. Rigosertib was first described as an inhibitor of the mitotic master regulator Polo-like kinase 1 (Plk1). However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras–Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes.This research was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/FEDER (doi:10.13039/501100011033), grants RTI2018-095496-B-I00 and PID2021-125705OB-I00, and by the Spanish Association Against Cancer (AECC) Scientific Foundation, grant LABAE16017DECA.Peer reviewe

From tumor-suppressor to oncogene: finding the oncogenic genetic determinants of the mitotic kinase Polo-Llike Kinase 1

Trabajo presentado en el II Congreso Anual de la Red Conexión Cáncer, celebrado en Benidorm (España) del 23 al 25 de enero de 2023

Identification of resistance mechanisms and vulnerabilities to the mitotic inhibitor Rigosertib (ON-01910.Na)

Trabajo presentado en el 18th ASEICA International Congress, celebrado en Santiago de Compostela (España) del 16 al 18 de noviembre de 2022

From tumor-suppressor to oncogene: finding oncogenic genetic determinants of the mitotic kinase Polo-like kinase 1

Trabajo presentado en el 18th ASEICA International Congress, celebrado en Santiago de Compostela (España) del 16 al 18 de noviembre de 2022

Identification of resistance mechanisms and vulnerabilities to the mitotic inhibitor Rigosertib (ON-01910.Na)

Trabajo presentado en el II Congreso Anual de la Red Conexión Cáncer, celebrado en Benidorm (España) del 23 al 25 de enero de 2023