title: Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition.
abstract: Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.
authors: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA [3] Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors: Aaron
authors: A
authors: Goldman
authors: 1] India Innovation Research Center, Bangalore 560099, India [2] Mitra Biotech Pvt Ltd, Narayana Nethrayala, Bangalore 560099, India.
authors: Biswanath
authors: B
authors: Majumder
authors: School of Medicine, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors: Andrew
authors: A
authors: Dhawan
authors: Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors: Sudharshan
authors: S
authors: Ravi
authors: 7730E BlackCrest Pl., Tucson, Arizona 85750, USA.
authors: David
authors: D
authors: Goldman
authors: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
authors: Mohammad
authors: 0000000306677269
authors: M
authors: Kohandel
authors: 1] India Innovation Research Center, Bangalore 560099, India [2] Mitra Biotech Pvt Ltd, Narayana Nethrayala, Bangalore 560099, India.
authors: Pradip K
authors: PK
authors: Majumder
authors: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA [3] Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [4] Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Shiladitya
authors: S
authors: Sengupta
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D047428:Protein Kinase Inhibitors; D043823:Taxoids; C080625:taxane