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Discovering the role of YES1 in triple negative breast cancer

Award Number: R01CA257502
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Discovering the role of YES1 in triple negative breast cancer - PROJECT SUMMARY/ABSTRACT SRC Family Kinases (SFKs) are a group of 9 non-receptor tyrosine kinases that mediate the effects of many extracellular and intracellular signaling pathways. While these proteins have often been considered to be functionally similar to SRC, the founding member of the family, it is now clear that they have non-redundant and unique activities. In cancer, these proteins are differentially expressed and their roles can even be antagonistic. This project launches from our discovery that one of these family members, YES1, is selectively overexpressed in Triple Negative Breast Cancer (TNBC), is associated with poor outcomes, and is necessary for sustained growth of TNBC cells. TNBC is a collection of highly aggressive diseases with limited therapeutic options primarily involving cytotoxic chemotherapy. While many patients initially respond to these treatments, resistance is common, resulting in poor patient outcomes. Thus, identifying vulnerabilities in this group of diseases is essential to yield approaches for improving survivorship. We propose that YES1 is one of these vulnerabilities. In preliminary data, we show that YES1 is essential for maintaining expression of Epidermal Growth Factor Receptor (EGFR) as well as ensuring mitotic fidelity. EGFR is a major driver of TNBC growth. When YES1 is depleted, EGFR is degraded and its signaling is lost. In addition, we report that YES1 silencing causes several nuclear defects including micro-, multi-, and dysmorphic nuclei indicating that YES1 is essential for accurate completion of mitosis. We hypothesize that these two functions of YES1 are essential for cellular viability in TNBC. Moreover, we propose that YES1 may be a useful therapeutic target to improve the efficacy of drugs targeting EGFR and mitosis. In Aim 1, we will determine how YES1 controls EGFR degradation and assess whether YES1 overexpression underlies resistance to EGFR inhibitors in TNBC. Aim 2 will focus on identifying specific events in mitosis that are impacted by YES1 and the mechanisms involved. It will also discern whether modulating YES1 can impact response to taxanes, mainstay chemotherapies for TNBC. Lastly, in Aim 3, we will determine if EGFR and YES1 participate in a feedforward loop that controls mitosis. This will involve interrogating the role of EGFR in mediating the effects of YES1 on mitosis and determining if EGFR is also an upstream regulator of YES1. Major innovations of this project include the identification of YES1 as a new oncogenic driver of TNBC, the discovery that YES1 and EGFR may control the genomic complexity that is associated with this disease, the therapeutic assessment of a novel inhibitor of YES1 in PDX models of TNBC, and the potential for improving the efficacy of EGFR inhibitors and taxanes in a disease that requires new therapeutic approaches to improve patient outcomes.


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: 2026 ( Subtotal = $0 )
2026	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	5	1/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $532,470 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	002	5	6/10/2025	NON-COMPETING CONTINUATION	$46,133
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	001	5	1/23/2025	SUPPLEMENT FOR EXPANSION	$64,023
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	5	1/22/2025	NON-COMPETING CONTINUATION	$415,201
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	003	5	9/5/2025	SUPPLEMENT FOR EXPANSION	$7,113
														Subtotal = $532,470

Issue Date FY: 2024 ( Subtotal = $875,887 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	4	1/4/2024	NON-COMPETING CONTINUATION	$415,201
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	001	4	1/5/2024	SUPPLEMENT FOR EXPANSION	$68,068
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	004	4	4/16/2024	SUPPLEMENT FOR EXPANSION	$3,782
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	002	4	2/12/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	005	4	9/6/2024	SUPPLEMENT FOR EXPANSION	$365,768
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	003	4	4/16/2024	NON-COMPETING CONTINUATION	$23,068
														Subtotal = $875,887

Issue Date FY: 2023 ( Subtotal = $483,424 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$452,109
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	001	3	9/13/2023	SUPPLEMENT FOR EXPANSION	$31,315
														Subtotal = $483,424

Issue Date FY: 2022 ( Subtotal = $452,109 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	001	2	5/25/2022	NON-COMPETING CONTINUATION	$36,908
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	2	1/13/2022	NON-COMPETING CONTINUATION	$415,201
														Subtotal = $452,109

Issue Date FY: 2021 ( Subtotal = $461,334 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Biology Research	000	1	1/29/2021	NEW	$461,334
														Subtotal = $461,334

Grand Total All Awards = $2,805,224

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Discovering the role of YES1 in triple negative breast cancer

Award Number: R01CA257502

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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