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Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies

Award Number: R00CA263194
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies - Project Summary/Abstract: The anaphase-promoting complex/Cyclosome (APC/C) is a well-defined multi-subunit E3 ubiquitin ligase that regulates targeted cell cycle regulators for degradation by the Ubiquitin Proteasome Pathway (UPP), promoting cell cycle progression from metaphase to anaphase and being involved in G1 phase maintenance. The APC/C E3 ligase complex is evolutionarily conserved and relies on two adaptor proteins, Cdc20 and Cdh1, to recognize different target proteins and regulate cell cycle progression. However, compared to Cdc20 that is subjected to Cdh1-mediated destruction, regulation of the E3 ligase activity of Cdh1 is not well known yet. Previous study has shown that there were 19 serine and threonine residues on Cdh1 that can be phosphorylated by multi-kinases in vivo, indicating that the phosphoregulation of Cdh1 is much more complex. In the present proposal, I found that CDK4 can phosphorylates Cdh1 in vitro and modulates its E3 ligase activity. Furthermore, we found that the phosphorylation of Cdh1 by CDK4 can be recognized by the Pin1 proline isomerase, facilitating Cdh1-Pin1 complex formation. In keeping with this notion, employment of the CDK4/6 inhibitor or mutating the phosphorylation sites can disrupt the Cdh1-Pin1 interaction. Consequently, Cdh1 can mediate Pin1 for polyubiquitination and degradation. As such, depletion of endogenous Cdh1 abolished the Pin1 inhibitor treatment induced Pin1 degradation in cells. Importantly, the Pin1 inhibitor-induced cell proliferation suppression was also abolished in Cdh1-null MEFs, suggesting the functional presence of Cdh1 is required for Pin1 inhibitor-induced cell proliferation suppression. In addition, combination of the CDK4/6 inhibitor and Pin1 inhibitor exhibits significantly enhanced suppressing effect in breast cancer cells. In the first Aim of this proposal, I am going to explore the role of CDK4 kinase in regulating the E3 ligase activity of Cdh1 (Aim #1). Therefore, the second Aim in this proposal will be exploring the potential role of Cdh1 in mediating Pin1 inhibitor treatment induced Pin1 protein destruction (Aim 2). Together, these results implicate a functional role of the CDK4/Cdh1/Pin1 signaling axis in regulating cell proliferation, and provide rational for combining the CDK4/6 inhibitor and Pin1 inhibitor to treat breast cancer.


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 = $248,999 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	5	7/20/2026	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2025 ( Subtotal = $248,999 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	4	7/23/2025	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2024 ( Subtotal = $248,999 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	3	7/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $746,997

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Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies

Award Number: R00CA263194

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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