MassIVE MSV000097698

Partial Public PXD063244

GPCR5D alterations provide proliferative advantage in multiple myeloma

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Description

Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target, although its physiological function remains undefined. Mono-allelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline mono-allelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled various GPRC5D genetic alterations to investigate their impact on myeloma cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that mono-allelic GPRC5D loss reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D induces transcriptional and phosphoproteomic reprogramming that promotes a proliferative phenotype and alters chemokine signaling. Clonal competition assays reveal that both functional and non-functional CAR-T cells preferentially select for GPRC5D-deficient cells. Collectively, our findings reveal that GPRC5D loss exerts a dual effect in MM by driving resistance to GPRC5D-targeted immunotherapies and enhancing tumor fitness through proliferative reprogramming. [doi:10.25345/C5H708C76] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: cancer ; Multiple myeloma ; Bottom-up proteomics ; GPRC5D ; Immunotherapies ; Bispecific antibodies ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Bernhard Kuster, Chair of proteomics and bioanalytics (Technical University of Munich), Germany
Submitting User: jthurner
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