Espinosa Gil, S. | Search bioRxiv

bioRxiv2026

ERK5 inhibition triggers CDK6 proteasomal degradation and enhances palbociclib efficacy in cancer cells

Advanced endometrial cancer (EC) and melanoma are two malignancies with poor treatment options at advanced stages. CDK4 and CDK6 kinases play a central role in the regulation of cell proliferation by controlling progression through G1/S transition. CDK4/CDK6 inhibitors are currently in clinical trials for advanced ECs, whereas melanoma tumors frequently carry mutations affecting the CDK4/CDK6 pathways that support the therapeutic potential of these kinases. The MAP kinase ERK5 promotes tumor progression by driving cell-cycle progression, yet its functional interplay with CDK4/6-dependent cell cycle control remains poorly defined. Here, we investigated the relationship between ERK5 and CDK4/6 in melanoma and serous EC cells, uncovering the benefits of their co-targeting. Both genetic and pharmacological inhibition of ERK5 induced CDK6 proteasomal degradation, without affecting CDK4 protein levels. Co-treatment with the ERK5 inhibitor JWG-071 and palbociclib synergistically reduced cell viability and increased apoptosis in both melanoma and EC cells, compared with single-agent treatments. Mechanistically, combined inhibition of ERK5 and CDK4/6 reinforced cell-cycle inhibitory signaling through p21 induction and reduced phospho-retinoblastoma levels. These findings suggest that targeting ERK5 may improve the anticancer efficacy of palbociclib, at least in melanoma and serous EC tumors.

cancer biology↗

bioRxiv2026

C1q from C1q+ tumor-associated myeloid cells promotes resistance to T-cell engagers and CAR T-cells and is induced by LIF and glucocorticoids

Immunotherapies, particularly T-cell engagers (TCEs) and CAR T-cells, have shown limited efficacy in solid tumors, partly due to an immunosuppressive tumor microenvironment (TME). However, the molecular mechanisms by which the TME impairs immunotherapy remain poorly understood. Here, we found that C1q generated by C1q tumor-associated myeloid cells (TAMs) plays a fundamental role in shaping the immunosuppressive TME in glioblastoma (GBM), one of the most aggressive tumors. C1q suppressed T-cell activation and impaired the activity of T-cell engagers (TCEs) and CAR T-cells. Genetic ablation of C1qa improved anti-tumor responses to TCEs and CAR T-cells. We used innovative patient-derived tumor tissue cultures (PDTTCs), which preserve an intact TME, from 19 GBM patients and identified the LIF cytokine as the main inducer of C1q. Moreover, we discovered that glucocorticoids cooperate with LIF to induce C1q. The identified C1q TAM signature overlapped with an anti-LIF gene signature, was associated with poor prognosis, and was enriched in mesenchymal GBMs with NF1 mutations. The blockade of LIF using an anti-LIF neutralizing antibody decreased the presence of C1q+ TAMs, and we found that the regulation of C1q by anti-LIF is conserved between human and mouse. Using the C1qa-/- GBM mouse model, we showed that C1q mediates the anti-tumor immune response induced by LIF blockade. Our findings identify C1q TAMs as key immunosuppressive players in GBM, impairing CAR T-cells and TCE activity, and position them as therapeutic targets to improve immunotherapy responses in this devastating disease.

cancer biology↗