GPCR-Driven Mechanisms of Tumor Progression and Therapy Resistance

Although G protein–coupled receptors (GPCRs) are highly druggable, their therapeutic potential in cancer has remained largely untapped, in part due to signaling redundancy. Our research addresses this challenge by targeting convergent downstream signaling nodes.

Supported by Department of Defense (DOD) awards and an NCI R01 grant, we discovered that Gi/o-coupled GPCRs are critical drivers of HER2⁺ breast cancer. We demonstrated that these receptors transactivate ErbB family signaling and promote cancer stem cell (CSC) self-renewal, fueling tumor growth and resistance to HER2-targeted therapies. Importantly, pharmacologic inhibition of Gi/o signaling suppressed tumor progression and re-sensitized resistant tumors to HER2-targeted agents, providing strong translational rationale.

We were also among the first to characterize the oncogenic potential of naturally occurring cancer-associated Gα mutations (GαoR243H and Gαi2R179C) in vivo. While insufficient to initiate tumors independently, these mutations function as potent metastatic drivers when combined with oncogenic events such as Neu activation or PTEN loss. Mechanistically, we identified c-Src activation as a key downstream effector, revealing a clinically actionable vulnerability in tumors harboring these mutations.

Defining the Roles of G Protein Regulators RACK1 and WDR26 in Cancer and Metabolism

Our laboratory has defined critical roles for the WD40 scaffold proteins WDR26 and RACK1 in both cancer and metabolic regulation.

Supported by a DOD grant and an ongoing NCI R01, we demonstrated that WDR26 is upregulated in approximately 30% of breast cancers and functions as an oncogene by amplifying Gβγ–PI3K/AKT signaling. Using mammary-specific knockout mouse models, we established that WDR26 is essential for tumor initiation and metastasis in HER2- and PyMT-driven breast cancer. Mechanistically, we discovered that WDR26 scaffolds the CTLH E3 ubiquitin ligase complex to promote degradation of the tumor suppressor SNF5, defining a previously unrecognized oncogenic axis and identifying disruption of the WDR26–CTLH interaction as a potential therapeutic strategy.

In prostate cancer, we found that RACK1 is markedly upregulated in high-grade tumors and required for tumorigenesis driven by PTEN/p53 loss. RACK1 deletion blocks AKT membrane recruitment and mTORC2 activation, disabling a key survival pathway without triggering compensatory androgen receptor signaling. These findings reveal a novel therapeutic entry point for selectively targeting PI3K/AKT-driven prostate cancer.

Beyond cancer, our work has uncovered unexpected roles for WDR26 and RACK1 in glucose metabolism. We demonstrated that RACK1 functions as a dual-compartment scaffold in hepatocytes, coordinating glucagon signaling and gluconeogenesis through spatial regulation of the GCGR–PKA–CREB axis. Additionally, our preliminary data suggest that WDR26, as a core component of the hepatic CTLH complex, may function as a metabolic “thermostat” that maintains systemic glucose homeostasis. Ongoing studies are investigating how the CTLH E3 ubiquitin ligase regulates hepatic glucose metabolism and contributes to diabetes development.