Ku, A. | Search bioRxiv

bioRxiv2025

TMPRSS2-ERG confers resistance to antiandrogens: mechanism and therapeutic implications

Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.

cancer biology↗

bioRxiv2022

PKC-alpha regulates the phosphorylation of KRAS that suppresses its oncogenic properties

Oncogenic KRAS-driven cancers have long been considered as "undruggable" due to limited therapeutic options. While the recent success of KRAS-G12C inhibitors argues against the "undruggability" of KRAS, this treatment only benefits a small proportion of patients with KRAS mutant cancers, leaving an urgent need for modalities to target other KRAS mutants. KRAS-calmodulin (CaM) signaling axis reportedly regulates the oncogenic properties of KRAS through its C-terminal hypervariable region. Phosphorylation of KRAS by activated protein kinase C (PKC) uncouples KRAS-CaM, resulting in growth inhibition effective against the entire spectrum of KRAS hotspot mutations. However, broadly activating PKC could mediate tumor promoting signaling nodes and cause systemic toxicity, undermining its applicability as an anti-KRAS therapy. Here, we found that prostratin induces KRAS phosphorylation, resulting in an elevated level of active CaM in the cytosol of KRAS mutant cells, and consequentially suppresses their malignancies. A whole-genome wide CRISPR/Cas9 knockout screening, further confirmed by biochemical analysis, revealed that prostratin acts through activating PKC. Functional studies confirmed PKC as the sole kinase to phosphorylate KRAS and, therefore, a KRAS suppressor. Activation of PKC induces senescence in KRAS mutant tumor cells through PTPN14, accompanied by a secretory phenotype contributing to the growth inhibition, and parallelly mediates a nuclear translocation of a CaM-dependent transcription activator, CAMTA-1, which can be a biomarker to indicate the activity of PKC-KRAS-CaM axis. Our findings reveal a previously understudied regulation of KRAS-CaM axis by PKC, which can be an actionable target for developing anti-KRAS therapeutics. One Sentence SummaryThis study deciphers a PKC-led tumor suppressive effect specific to the "undruggable" KRAS-mutant tumor cells through the phosphorylation of KRAS and a consequently altered KRAS-CaM signaling axis.

cancer biology↗