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GPCR5D alterations provide proliferative advantage in multiple myeloma

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bernhard Kuster

PROVIDER: MSV000097698 | MassIVE | Wed Apr 23 06:17:00 BST 2025

SECONDARY ACCESSION(S): PXD063244

REPOSITORIES: MassIVE

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