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Targeting PLK1 in myelodysplastic syndromes: The Role of Rigosertib in Precision Medicine
Vedant Patil1, Sujata Lambe1, Anand Lokhande1
1Department of Pharmaceutical Chemistry, SMBT College of pharmacy, Nandi-hills, Dhamangaon, Tal: Igatpuri, Dist: Nashik - 422403, India.
Abstract:
Rigosertib (ON 01910.Na) is a novel multi-kinase inhibitor initially developed as a non-ATP competitive agent, targeting dysregulated signalling pathways in cancer cells, notably RAS/RAF/MEK/ERK and PI3K/AKT, alongside Polo-like kinase 1 (PLK1). Preclinical studies have demonstrated its potent anticancer effects across various malignancies, including myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML), and solid tumours such as pancreatic, colorectal, and breast cancers, by inducing apoptosis, mitotic arrest, and oxidative stress. Its selective cytotoxicity spares normal cells, making it a promising therapeutic candidate. However, clinical trials have yielded mixed results; while early-phase studies showed promise, particularly in hematologic cancers, phase III trials, such as those in MDS and pancreatic cancer, failed to demonstrate significant survival benefits over standard treatments. Challenges include variable patient responses, potential resistance mechanisms, and manageable but notable toxicities like myelosuppression and fatigue. Emerging evidence suggests rigosertib's potential in paediatric cancers like neuroblastoma and its synergy with therapies such as MEK inhibitors and hypomethylating agents. Future research should focus on optimizing combination strategies, identifying predictive biomarkers, and improving drug delivery to enhance its clinical efficacy and applicability across diverse cancer types.
Insights
Rigosertib, a multi-kinase inhibitor, shows preclinical anticancer promise but mixed clinical trial results. Future research focuses on optimizing combinations and biomarkers for diverse cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rigosertib is a novel multi-kinase inhibitor targeting key cancer signaling pathways like RAS/RAF/MEK/ERK and PI3K/AKT.
- It also inhibits Polo-like kinase 1 (PLK1), crucial for cell division.
- Preclinical data show potent anticancer activity in various hematologic and solid tumors.
Purpose of the Study:
- To review the preclinical and clinical development of rigosertib.
- To evaluate its efficacy, safety, and potential in different cancer types.
- To identify challenges and future directions for rigosertib's therapeutic application.
Main Methods:
- Review of preclinical studies demonstrating rigosertib's mechanism of action and anticancer effects.
- Analysis of clinical trial data from early-phase and Phase III studies in hematologic malignancies and solid tumors.
- Evaluation of reported toxicities and emerging combination strategies.
Main Results:
- Rigosertib demonstrated significant preclinical efficacy by inducing apoptosis and mitotic arrest, with selective toxicity.
- Early clinical trials showed promise, especially in hematologic cancers.
- Phase III trials in myelodysplastic syndromes and pancreatic cancer did not meet primary endpoints for survival benefit.
Conclusions:
- Rigosertib exhibits a promising preclinical profile but has faced challenges in demonstrating significant clinical survival benefits.
- Variable patient responses, resistance, and toxicities necessitate further investigation.
- Optimizing combination therapies, identifying predictive biomarkers, and improving drug delivery are key for future clinical success.
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