Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

TLDR

Adaptive resistance models are crucial to overcoming cancer chemotherapy failure. The study demonstrates that taxane exposure drives breast cancer cells into a transient CD44^hiCD24^hi chemotherapy‑tolerant state. The transition involves CD44/CD24 clustering in lipid rafts that activates SFK/Hck signaling and inhibits apoptosis. Sequential administration of SFK/Hck inhibitors after taxane treatment sensitizes tolerant cells, suggesting a translational strategy to improve antitumor outcomes.

Abstract

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.