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GABARAP Deficiency May Contribute to Bortezomib Resistance in Multiple Myeloma

June 6, 2024

July 2024

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

Loss of GABA type A receptor-associated protein (GABARAP), a well-known regulator of autophagy and vesicular trafficking, was associated with impaired immunogenic cell death signaling and shorter multiple myeloma (MM) survival, according to a study published in Blood.

“Resistance to immunogenic cell death can significantly impact patient outcomes,” said study researcher Annamaria Gulla, MD, of Candiolo Cancer Institute in Italy and Dana-Farber Cancer Institute in Boston. For example, the proteasome inhibitor bortezomib works against MM not only by directly killing myeloma cells but also by inducing immunogenic cell death. “Restoring tumor immunogenicity presents an ideal strategy for addressing immunosuppression in cancer and achieving effective tumor clearance.”

Dr. Gulla and colleagues integrated patient transcriptomic and proteomic data to identify genes that affected the exposure of the “eat-me” signal calreticulin (CRT), potentially causing resistance to immunogenic chemotherapy.

They performed this analysis before and after bortezomib exposure, focusing on proteins enriched after treatment. GABARAP and carnitine palmitoyl transferase 1A (CPT1A) were both identified as binding partners of CRT during the immunogenic cell death process; both had lower expression among patients with worse clinical outcomes.

This was tested in two additional independent datasets, which showed that only lower expression of GABARAP, the gene locus of which is on chromosome 17p, was associated with worse clinical outcomes in patients with MM.

The study also showed that although GABARAP was downregulated in all patients with MM compared with the general population, it was significantly lower in patients whose disease had del(17p).

“The contribution of some of the genes lost with the deletion of 17p is not well known,” Dr. Gulla said. “Bortezomib treatment in these patients may be less effective due to an associated lack of spontaneous and immunogenic cell death-mediated anti-tumor immunity.”

Even after excluding patients with MM with del(17p), the prognostic significance of low GABARAP expression remained. Additionally, analysis of the Cancer Genome Atlas database showed that low GABARAP levels were associated with worse outcomes in other cancers, such as lower-grade glioma and pancreatic adenocarcinoma.

Using MM cell lines, the researchers found that GABARAP deletion impaired the “eat-me” signal of CRT on the surface of dying MM cells, “reducing tumor cell phagocytosis by dendritic cells and the subsequent anti-tumor T-cell response.”

“Since bortezomib kills MM cells in an immunogenic fashion, resistance may be derived not only from resistance to cell death and defective host immunity but also from a cell’s death not being immunogenic enough to trigger anti-tumor immunity,” Dr. Gulla explained. “This work highlights a novel mechanism by which MM cells can develop resistance to the immunogenic effect of bortezomib treatment.”

The investigators found that GABARAP blocked immunogenic cell death signaling by decreasing autophagy and altering Golgi apparatus morphology; however, experiments showed that upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and immunogenic cell death signaling in GABARAP knocks out cells undergoing bortezomib treatment.

The researchers posited that combining an autophagy inducer, like rapamycin, with an immunogenic cell death inducer, like bortezomib, could improve outcomes for patients with MM or other cancers with low GABARAP levels.

Dr. Gulla said additional studies are required to assess the effect of combining bortezomib with autophagy inducers on immune effectors and regulators and to define the optimal therapeutic approach for translation into the clinic.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Gulla A, Morelli E, Johnstone M, et al. Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma [published online ahead of print, 2024 March 29]. Blood. doi: 10.1182/blood.2023022777.

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