Analysis of cellular models of clonal evolution reveals co-evolution of imatinib and HSP90 inhibitor resistances.

Autor: Arolla RG; Molecular Biology Laboratory, CPMB, Osmania University, Hyderabad, 500007, India., Malladi S; Molecular Medicine and Therapeutics Laboratory, CPMB, Osmania University, Hyderabad, 500007, India., Bhaduri U; Chromatin Biology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore, 560064, India., Gayatri MB; Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India., Pattamshetty P; Department of Genetics and Molecular Medicine, Vasavi Medical and Research Centre, Hyderabad, 500034, India., Mohan V; Department of Genetics and Molecular Medicine, Vasavi Medical and Research Centre, Hyderabad, 500034, India., Katika MR; Nizam's Institute of Medical Sciences, Hyderabad, 500082, India., Madhava Reddy AB; Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India., Satyanarayana Rao MR; Chromatin Biology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Center for Advanced Scientific Research, Bangalore, 560064, India., Vudem DR; Molecular Biology Laboratory, CPMB, Osmania University, Hyderabad, 500007, India., Kancha RK; Molecular Medicine and Therapeutics Laboratory, CPMB, Osmania University, Hyderabad, 500007, India. Electronic address: ickrishna@gmail.com.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2021 Jan 01; Vol. 534, pp. 461-467. Date of Electronic Publication: 2020 Nov 25.
DOI: 10.1016/j.bbrc.2020.11.059
Abstrakt: Treatment relapse due to clonal evolution was shown to be an independent factor for poor prognosis in advanced stages of chronic myeloid leukemia. Overcoming secondary resistance arising due to clonal evolution is still an unmet need and lack of adequate pre-clinical models hampers the identification of underlying mechanisms and testing of alternate treatment strategies. The current study thus aimed to create cellular models to study molecular mechanisms underlying clonal evolution and identify strategies to overcome the secondary drug resistance. Analysis of cell lines derived from three independent cell-based screens revealed the co-evolution specifically of imatinib and HSP90 inhibitor (HSP90i) resistances despite their exposure to a single inhibitor alone. Molecular and biochemical characterization of these cell lines revealed additional cytogenetic abnormalities, differential activation of pro-survival signaling molecules and over expression of ABL kinase and HSP90 genes. Importantly, all the imatinib-HSP90i dual resistant cell lines remained sensitive to sorafenib and vorinostat suggesting their utility in treating patients who relapse upon imatinib treatment due to clonal evolution. In addition, we cite similar examples of dual resistance towards various kinase inhibitors and HSP90i in some cell lines that represent solid cancers suggesting co-evolution leading to secondary drug resistance as a pan-cancer phenomenon. Taken together, our results suggest the efficacy of HSP90i in overcoming drug resistance caused by point mutations in the target kinase but not in cases of clonal evolution.
Competing Interests: Conflicts of interest The authors declare no potential conflicts of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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