Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced
Aaron Goldman1, Biswanath Majumder2, Andrew Dhawan3
11] 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.
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.
Insights
Chemotherapy resistance in cancer can be overcome by targeting a specific cell state. Inhibiting Src Family Kinase (SFK) after taxane treatment sensitizes resistant cancer cells to chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Adaptive resistance is a major challenge in cancer chemotherapy.
- Understanding the mechanisms of chemotherapy failure is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the mechanisms of taxane-induced adaptive resistance in breast cancer.
- To identify therapeutic strategies to overcome chemotherapy tolerance.
Main Methods:
- Utilized human breast cancer explants, in vitro cell lines, and mouse in vivo models.
- Employed mathematical modeling to analyze phenotypic cell state transitions.
- Investigated the role of CD44, CD24, and Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) in chemotherapy tolerance.
Main Results:
- Taxane exposure induces a transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state.
- This state involves CD44/CD24 clustering in lipid rafts, activating SFK/Hck and suppressing apoptosis.
- Post-taxane administration of SFK/Hck inhibitors, but not co-administration, sensitized tolerant cells to chemotherapy.
Conclusions:
- Chemotherapy-induced phenotypic cell state transition is a targetable mechanism for overcoming resistance.
- Temporally constrained inhibition of SFK/Hck offers a potential translational strategy to improve anti-tumor outcomes in cancer management.
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