Alon Goren, Assistant Professor at UC San Diego, in collaboration with Trey Ideker. Dynamic protein complexes and transient protein-protein interactions (PPI) are integral for the vast majority of normal and cancer associated processes such as cellular metabolism, signal transduction networks and regulation of chromatin structure. Importantly, in cancer, this complex organization is involved in processes such as tumor initiation, progression and metastasis. Yet, current methods cannot not fully capture this complexity; our inability to simultaneously detect the multiple dynamic interactions occur in different conditions is a major roadblock in addressing the CCMI goals of comprehensively map the molecular networks that underlie cancer and advance precision medicine.

To fill this gap, we are developing a novel method, Prod-seq that enables simultaneous identification and characterization of multiple interactions between proteins within functional complexes. This transformative tool will allow high-throughput queries of the dynamic interactions of proteins, and expands the focus from single interactions towards an unprecedented, multi-dimensional interrogation of the cellular complexity. We will use head and neck squamous cell carcinoma (HNSCC) cells and employ Prod-seq to generate interaction and abundance maps of key proteins studied by the Ideker Lab leveraging the PPI datasets generated as references for validating and optimizing our results.

Natalia Jura, Assistant Professor at UCSF, in collaboration with Nevan Krogan. The catalytically inactive HER3 receptor tyrosine kinase is a multi-site scaffold for the phosphoinositide-3 kinase (PI3K), whose downstream signaling to Akt constitutes one of the most frequently deregulated pathway in human cancer, including head and neck cancer. Recent studies in the laboratory of Dr. Nevan Krogan (UCSF) led to a discovery that a subset of PI3KCA mutant variants in head and neck cancer cells preferentially associate with the HER3 receptor. Moreover, these PI3KCA mutants are dependent on HER3 binding to elicit its oncogenic signaling. These exciting findings point to a unique mechanism by which HER3 activates PI3KCA, whose understanding will help develop personalized therapies for the affected patients. At present, the nature of this selectivity is unknown due to the lack of direct insights into the mechanism of PI3KCA/HER3 binding. This project aims to address this gap through the biophysical characterization of the PI3KCA/HER3 interaction and its modulation by the cancer mutations. The proposed work will provide a platform for the development of specific inhibitors that disrupt the signaling junction between HER3 and PI3K in disease.