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Dissecting the role and mechanism of EML4-ALK condensates in oncogenic signaling and tumor growth

Award Number: R01CA279180
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Dissecting the role and mechanism of EML4-ALK condensates in oncogenic signaling and tumor growth - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $670,212 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	3	3/5/2025	NON-COMPETING CONTINUATION	$603,191
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$67,021
														Subtotal = $670,212

Issue Date FY: 2024 ( Subtotal = $636,702 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$33,511
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	2	3/5/2024	NON-COMPETING CONTINUATION	$603,191
														Subtotal = $636,702

Issue Date FY: 2023 ( Subtotal = $670,214 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	1	4/11/2023	NEW	$670,214
														Subtotal = $670,214

Grand Total All Awards = $1,977,128

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Dissecting the role and mechanism of EML4-ALK condensates in oncogenic signaling and tumor growth

Award Number: R01CA279180

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/11/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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