Targeting regulators of lipogenesis in drug-tolerant persister cells

Abstract

Glioblastoma is a fatal brain tumour, with a median survival of less than 15 months. There has been no change to the standard-of-care since 2005.

CMPD1 is a small-molecule microtubule-targeting agent with a cytotoxic effect on glioblastoma cells. However, a subpopulation of cells can survive CMPD1 exposure, termed drug-tolerant persister cells (DTPs). Upon treatment withdrawal, DTPs regain the same chemosensitivity as treatment-naïve cells, using reversible and transient mechanisms to withstand therapy.

We questioned whether activation of LXR, a nuclear receptor regulating cholesterol homeostasis and lipid metabolism, could reduce the number of surviving persister cells. We found that CMPD1 and LXR agonist combination therapy decrease persister cell survival, potentially through lipogenesis.

A lipidomic screen of CMPD1-tolerant cells revealed that CMPD1 induces lipidomic reprogramming. DTPs exhibit low SCD1 expression, an enzyme desaturating saturated fatty acids into monounsaturated fatty acids. Investigation into lipid-associated behaviours in DTPs revealed increased lipid saturation, heightened membrane rigidity and activation of the unfolded protein response - a possible consequence of low SCD1 expression.

Hence, we overexpressed SCD1 in glioblastoma stem cells at two different levels, demonstrating that various levels of SCD1 overexpression can either reduce or increase the number of surviving CMPD1-tolerant persisters compared to CMPD1-treated cells with endogenous SCD1 expression. Investigation in naïve cells showed different levels of SCD1 overexpression regulate behaviours including membrane fluidity, proliferation and triglyceride levels.

However, targeting LXR and SCD1 did not eliminate all persister cells, prompting us to investigate whether persister cell survival is influenced by cellular heterogeneity. We found that naïve RKI1-derived clones exhibit differential sensitivity to CMPD1, which were associated with transcriptomic differences.