MAST1 inhibitors to overcome resistance to platinum-based chemotherapy, exacerbated by dexamethasone co-administration.
- Co-administration of MAST1 inhibitor and MAST1-stabilizing protein inhibitor abrogates tumor resistance to cisplatin
- MAST1 inhibitor, lestaurtinib, has previously reached phase III clinical trials and proven safe in humans
- Hsp90B (MAST1 stabilizer) inhibitor, 17-AAG, has previously reached phase III clinical trials and proven safe in humans
An estimated 1.8 million men and women were diagnosed with cancer in 2020. Platinum-based drugs, including cisplatin, are regularly prescribed for the treatment of a variety of cancers. However, this treatment often becomes ineffective due to the development of resistance. This resistance is intensified by dexamethasone, which is prescribed along with platinum-based drugs for side effect management. Patients with chemotherapy-resistant cancers have extremely poor prognosis and limited alternatives.
Cisplatin resistance is mediated by MAST1 expression, which is triggered by cisplatin and exacerbated by dexamethasone, which is co-administered for side effect management. MAST1 activates a pro-survival pathway and is protected from degradation by heat protein, hsp90B. Emory researchers conducted experiments on mice with xenografted patient-derived tumors and found that co-administration of a MAST1 inhibitor (lestaurtinib) and a hsp90B inhibitor (17-AAG) with cisplatin arrested tumor growth more extensively than cisplatin treatment alone. Furthermore, co-administration of lestaurtinib alone was able to abrogate the reduction in tumor arrest observed with the addition of dexamethasone to cisplatin treatment. These preliminary studies suggest that targeting MAST1 and hsp90B with lestaurtinib and 17-AAG is an effective strategy to overcome cisplatin and combined cisplatin and dexamethasone resistance.
In vivo xenograft studies in mice show reduction in tumor growth with the addition of lestaurtinib and 17-AAG to cisplatin therapy.
Publication: Pan, C., Kang, J., Hwang, J.S. et al. (2021). Nat Commun 12, 4960