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Principal Investigator: Trever G Bivona
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $636,702
Funding agency: National Cancer Institute
PROJECT ABSTRACT. Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung
cancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset
of NSCLC. 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 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
(condensates) as a distinct mechanism of oncogenic kinase signaling in cancer. Our data suggest an emerging
paradigm in which certain ALK fusion oncoproteins, as well as other clinically-relevant oncoprotein kinase fusions
such as RET fusions, form de novo their own phase separated protein-based subcellular compartment devoid
of lipid membranes and utilize higher-order protein assembly as distinguishing principles underlying oncogenic
output. These membraneless cytoplasmic protein granules 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 use classical lipid membrane-based signaling. The pathogenic biomolecular condensates
formed by ALK (and other RTK) 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. For instance, protein granule formation
requires the adaptor proteins GRB2 and SHC, in addition to the ALK fusion oncoprotein. Our findings reveal
membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing
oncogenic RTK and RAS signaling in cancer. We propose 2 complementary Specific Aims using innovative
methodologies to probe condensate biology to understand the role of phase separation in ALK fusion oncogenic
signaling. We further define the protein architecture of ALK fusion protein granules and identify the key interacting
proteins required for ALK fusion protein granule formation, oncogenic signaling and tumor growth. The proposed
studies will establish a mechanistic understanding of RTK fusion condensate biology to lay a firm foundation for
the future design of mechanism-based therapeutic strategies to interfere with ALK protein granule assembly per
se and that complement conventional ALK-targeted clinical agents, which are ALK kinase inhibitors. This project
will provide insight into this distinct form of oncogenic signaling with a focus on ALK, with broader implications
for the understanding of condensate and RTK fusion biology and the design of differentiated treatment strategies.
Terms: <ALK gene><ALK protein><ASH Protein><Abundant SRC Homology><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Anaplastic Lymphoma Kinase Ki-1><Applications Grants><Architecture><Biological><Biology><CD246 Antigen><Cancer Cause><Cancer Control><Cancer Control Science><Cancer Etiology><Cancer Patient><Cancers><Cell Body><Cell Communication and Signaling><Cell Membrane Lipids><Cell Signaling><Cells><Chimera Protein><Chimeric Proteins><Clinical><Complement><Complement Proteins><Complex><Cytoplasmic Granules><Cytoplasmic Protein><DNA Rearrangement><Data><Development><Drug resistance><EGF Receptor><EGFR><ERBB Protein><Engineering / Architecture><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Extracellular Signal-Regulated Kinase Gene><Foundations><Fusion Oncogene Proteins><Fusion Protein><Future><GRB-2><GRB2><GRB2 Protein><GRB2 adaptor protein><GRB2 gene><Gene Rearrangement><Generalized Growth><Genetic><Genetics-Mutagenesis><Goals><Grant Proposals><Growth><HER1><HLA-DR Associated Protein II><Histologic><Histologically><IGAAD><Inhibitor of GZMA-Activated DNase><Intracellular Communication and Signaling><Kinases><Lung Adenocarcinoma><MAP Kinase Gene><MAPK><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Membrane><Membrane Lipids><Methodology><Mitogen-Activated Protein Kinase Gene><Molecular><Mutagenesis><Mutagenesis Molecular Biology><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogene Products><Oncogene Proteins><Oncogenic><Oncoproteins><Outcome><Output><PTK Receptors><Pathogenicity><Pathway interactions><Patients><Phase><Phenotype><Phosphatase 2A Inhibitor I2PP2A><Phosphotransferase Gene><Phosphotransferases><Physical condensation><Proteins><Proteomics><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recurrence><Recurrent><Role><SET Translocation Inhibitor-2 of Protein Phosphatase-2A><Set protein><Signal Transduction><Signal Transduction Systems><Signaling><TGF-alpha Receptor><Template Activating Factor I Beta><Testing><Therapeutic><Tissue Growth><Transforming Growth Factor alpha Receptor><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Urogastrone Receptor><Variant><Variation><Work><abundant Src homology protein><adapter protein><anaplastic lymphoma kinase><anaplastic lymphoma kinase gene><biologic><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer cell><clinical relevance><clinically relevant><complementation><condensation><design><designing><developmental><drug resistant><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><fusion oncoprotein><genetic approach><genetic strategy><granule><growth factor receptor-bound protein 2><improved><innovate><innovation><innovative><insight><kinase inhibitor><lung cancer><malignancy><membrane structure><mortality><multidisciplinary><mutant><neoplasm/cancer><ontogeny><pathway><precision medicine><precision-based medicine><protein expression><proto-oncogene protein c-erbB-1><recruit><resistance to Drug><resistant to Drug><response><social role><tool><treatment strategy><tumor growth>