Biology subjects

Beijnen, J. H.

Publications and source records attributed to Beijnen, J. H..

3 recordsLinked to original sources

bioRxiv2024

Mitochondrial damage triggers therapy-induced senescence

Glioblastoma (GBM) is a fatal brain tumor with a critical need for better therapies. It is known that the PI3K, MAPK, and CDK4/6 signaling pathways are hyper-activated in these tumors; however, previous studies have used very high concentration of inhibitors to assess their importance, with mixed results. Here we developed PMCi, a combination approach that targets all three pathways simultaneously, at clinically-relevant doses. PMCi effectively suppresses GBM cell proliferation in vitro and in vivo, and outperforms monotherapies and dual combinations. PMCi acts by inducing cellular senescence, which is mediated solely by the mitochondria, and, unlike other forms of senescence, is independent of nuclear damage. This phenotype is caused by a reactive oxygen species (ROS)\cGAS-STING\senescence-associated secretory phenotype (SASP) signaling cascade, that acts in a paracrine manner to establish and maintain senescence. Our results demonstrate that mitochondrial damage is sufficient to drive senescence, and that this can be leveraged to target GBM cells.

cell biology↗

bioRxiv2024

Disconnect between in vitro and in vivo efficacy of the MPS1 inhibitor NTRC 0066-0 against glioblastoma

PurposeGlioblastoma (GBM) is the most common adult primary brain tumor for which new therapeutic strategies are desperately needed. Monopolar spindle 1 (MPS1) is a mitotic kinase that plays a pivotal role in the spindle assembly checkpoint (SAC). GBM appears to be dependent on SAC fidelity, as MPS1 is overexpressed in many GBM patients. Thus, inhibiting MPS1 seems a viable therapeutic strategy to enhance mitotic cell death by attenuating SAC fidelity. NTRC 0066-0 is an MPS1 inhibitor that combines low nanomolar potency with a relatively long on-target residence time. MethodsWe here investigate the potential of NTRC 0066-0 as monotherapy and in combination with chemo-radiation for treatment of GBM using various in vitro and orthotopic in vivo models. ResultsWe show that NTRC 0066-0 efficiently induces GBM cell death in vitro, following continuous exposure with IC50s in the low nanomolar range. In contrast to previous reports of studies with other MPS1 inhibitors, we did not observe synergy in vitro with anti-microtubule drugs, such as docetaxel and vincristine. We demonstrate that NTRC 0066-0 has a high brain penetration, despite being a substrate of the efflux transporter P-glycoprotein. However, even when using recipient Abcb1a/b;Abcg2-/- mice with superior brain penetration and administering NTRC 0066-0 using a dose-dense regimen, we did not observe antitumor efficacy against an orthotopic GBM mouse model, neither as monotherapy nor in combination with standard-of-care temozolomide chemotherapy and radiotherapy. ConclusionThese data indicate that GBM is probably not a suitable indication for developing MPS1 inhibitors.

cancer biology↗

bioRxiv2022

Acquired and intrinsic resistance to vemurafenib in BRAFV600E-driven melanoma brain metastases

PurposeBRAFV600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We here tested the hypothesis that the drug efflux transporters P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) expressed at the blood-brain barrier (BBB) offer MBMs protection from therapy. MethodsWe intracranially implanted A375 tumor cells in wild-type and Abcb1a/b;Abcg2-/- mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib administration and determined the efficacy against brain metastases and subcutaneous lesions. ResultsAlthough contrast-enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs in Abcb1a/b;Abcg2-/- mice compared to wild-type mice. Concordantly, P-gp and BCRP are expressed in MBM-associated brain endothelium both in patients and in A375 xenografts and limited vemurafenib penetration into A375 MBMs. Confirming the BBB-specific context of this protection, vemurafenib was equally effective against subcutaneous A375 tumors in WT and Abcb1a/b;Abcg2-/- mice. Intriguingly, although initially responsive, A375 MBMs rapidly developed therapy resistance, even in Abcb1a/b;Abcg2-/- mice, and this was unrelated to pharmacokinetic or target inhibition issues. Rather, MBMs likely resorted to noncanonical growth signaling, as target inhibition of canonical MAPK pathway signaling components was maintained in resistant intracranial A375 tumors. ConclusionsWe demonstrate that BRAFV600E-driven MBMs are partly intrinsically protected from vemurafenib by the BBB. Intriguingly, MBMs can also rapidly acquire resistance in situ, likely by resorting to non-canonical growth signaling.

pharmacology and toxicology↗