Trever Bivona, MD, PhD
University of California, San Francisco
San Francisco
Currently available ALK inhibitors are an effective treatment for lung cancer, but tumors can development treatment resistance. In this project, Dr. Bivona will explore a novel way to treat ALK-positive lung cancer by targeting “membraneless cytoplasmic protein granules,” a new mechanism of signaling in ALK-positive lung cancer. His team will use precision medicine approaches that are complementary to current ALK inhibitors and that could improve their efficacy as well as quality of life for patients.
Research Summary
Precision medicines that specifically target anaplastic lymphoma kinase (ALK) gene fusions that drive cancer growth are leading to improved responses and quality of life in many ALK gene fusion positive (i.e., ALK positive) lung cancer patients. While current ALK inhibitors are highly effective, they are not curative in most patients because treatment resistance arises. The studies in this research project focus on the characterization of a new mechanism of oncogenic signaling in cancer that centers on ALK gene fusions in lung cancer. The overall goal we aim to achieve in this project is to create an entirely new approach to treat ALK positive lung cancer by developing a suite of precision therapies that are distinct in their mechanism of action against ALK and that can complement all current conventional ALK inhibitors and even improve their effectiveness, while maintaining safety and quality of life for patients. The work accomplished in this project could yield molecular treatments that better control, or potentially cure, ALK positive lung cancer through improved precision medicine.
Technical Abstract
ALK gene rearrangements (e.g., EML4-ALK fusions) are validated targets in NSCLC and current ALK kinase inhibitors yield impressive responses. Despite this clinical progress drug resistance remains a problem that limits patient survival. Improved therapeutic strategies are critical to identify to improve clinical outcomes. We propose an innovative, multidisciplinary, and collaborative project to hopefully improve the survival of ALK positive NSCLC patients by defining a new mechanism of oncogenic signaling that we uncovered by studying ALK fusion oncoproteins. We aim to capitalize on our discovery of membraneless cytoplasmic protein granules as a distinct mechanism of oncogenic kinase signaling in cancer. Our data suggest a new paradigm in which certain ALK fusion oncoproteins form de novo their own protein-based subcellular compartment devoid of lipid membranes and utilize higher-order protein assembly as distinguishing principles underlying oncogenic output. These properties comprise a mode of oncogenic signaling that is different from that of native receptor tyrosine kinase (RTK) signaling and oncogenic, mutant forms of other RTKs such as EGFR, which both use classical lipid membrane-based signaling. The pathogenic biomolecular condensates formed by ALK fusion oncoproteins locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in cells. We identified a set of protein granule signaling components and established structural rules that define ALK protein granule formation. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. We propose 3 Specific Aims to further unveil key interacting proteins required for ALK fusion protein condensate formation and signaling, characterize compartmentalized protein-protein interactions (PPIs) that drive condensate formation and/or oncogenic signaling, and identify pharmacologic strategies using existing agents to target the key PPIs required for driving this pathogenic biomolecular condensate formation and relaying the oncogenic signaling underlying the biology of ALK-driven NSCLC. The proposed studies could allow for mechanism-based therapeutic strategies to interfere with ALK protein granule assembly per se and that complement current ALK-inhibitors, which are kinase activity inhibitors. The pharmacologic agents we profile include clinical drugs and could be re-purposed and/or chemically optimized readily for clinical translation. This project will provide insight into ALK fusion biology and potential strategies to better control, or even cure, ALK-driven NSCLC.