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

• Published in: Biochemical and biophysical research communications Vol. 534; pp. 461 - 467
• Main Authors: Arolla, Rajender Goud, Malladi, Shweta, Bhaduri, Utsa, Gayatri, Meher Bolisetti, Pattamshetty, Preethi, Mohan, Vasavi, Katika, Madhumohan Rao, Madhava Reddy, Aramati Bindu, Satyanarayana Rao, Manchanahalli R., Vudem, Dashavantha Reddy, Kancha, Rama Krishna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021
• Subjects: Antineoplastic Agents - pharmacology; Cell Line, Tumor; Chromosome Aberrations - drug effects; Chronic myeloid leukemia; Clonal evolution; Clonal Evolution - drug effects; Drug repurposing; Drug resistance screen; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 inhibitors; Humans; Imatinib; Imatinib Mesylate - pharmacology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Transcriptome - drug effects; Clonal evolution; Drug repurposing; Imatinib; Drug resistance screen; Chronic myeloid leukemia; HSP90 inhibitors
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.11.059

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.
•Novel strategy of cell-based reciprocal screens to identify parallel evolution of drug resistances.•∙Identification of inherent resistance towards a drug when selected for the resistance for a different drug.•∙Demonstration of the efficacy of sorafenib and vorinostat in overcoming resistance caused due to clonal evolution.•∙Efficacy of HSP90 inhibition to overcome imatinib resistance arising due to mutation in ABL kinase but not due to clonal evolution.