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The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC

Award Number: R37CA249305
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC - PROJECT SUMMARY Cisplatin is one of the most effective and widely used anti-cancer drugs. For small cell lung cancer (SCLC), the current platinum-based standard treatment has not changed for more than three decades. Robust initial clinical response is usually observed in SCLC patients but the majority of patients succumb to chemoresistant recurrence. Despite tremendous efforts have been made to understand how SCLC cells develop cisplatin resistance, the precise mechanism remains elusive. As a part of our larger effort to decipher the mechanism of chemo-resistance, we employed a kinome wide shRNA screening and identified microtubule-associated serine/threonine kinase 1 (MAST1) as a “synthetic lethal” partner of cisplatin in SCLC. Using both SCLC cell lines and patient-derived tumors (PDX), we have demonstrated that MAST1 knockdown sensitizes ASCL1-high SCLC cells to cisplatin treatment in vitro and in vivo. Mining of CCLE database further shows that MAST1 expression is elevated in ASCL1-high subtype SCLC and positively correlates with cisplatin resistance in ASCL1-high SCLC cell lines. Through transcription factor profiling and unbiased datamining, we discovered that cisplatin physically binds and stabilize NFIB protein, a SCLC driver associated with disease progression, to promote MAST1 expression. Indeed, knockdown of NFIB blocked MAST1 induction by cisplatin, suggesting that MAST1 may be a downstream target of NFIB in SCLC. Our mass spectrometry based interactome study further showed CDK1 may be a novel upstream kinase for NFIB. Indeed, CDK1 directly phosphorylates NFIB and inhibition of CDK1 activity reduced NFIB level, which can be rescued by MLN4924 that inhibits Cullin-RING E3 ubiquitin ligases. This observation indicates that CDK1 may regulate NFIB stability through Cullin-RING E3 ubiquitin ligases. Our central hypothesis is that CDK1 directly phosphorylates NFIB to regulate its function, which globally regulates chromatin accessibility and consequently impacts cisplatin resistance in SCLC. We will test our hypothesis through the following aims: (1) To uncover the functional role of CDK1-NFIB signaling in SCLC. (2) To delineate the downstream network governed by NFIB. (3) To explore MAST1-regulated downstream signaling that promotes cell cycle progression, cell survival and cisplatin resistance.


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 = $375,936 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	002	6	6/23/2025	EXTENSION WITH OR WITHOUT FUNDS	$37,593
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	6	2/13/2025	EXTENSION WITH OR WITHOUT FUNDS	$338,343
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	5	6/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,936

Issue Date FY: 2024 ( Subtotal = $336,246 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$17,699
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	5	12/22/2023	NON-COMPETING CONTINUATION	$318,547
														Subtotal = $336,246

Issue Date FY: 2023 ( Subtotal = $329,410 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	4	12/20/2022	NON-COMPETING CONTINUATION	$318,547
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	002	4	3/15/2023	NON-COMPETING CONTINUATION	$28,316
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	001	2	2/27/2023	NON-COMPETING CONTINUATION	-$17,453
														Subtotal = $329,410

Issue Date FY: 2022 ( Subtotal = $367,692 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	002	3	3/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$367,692
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	005	3	4/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$505,893
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	003	2	4/28/2022	NON-COMPETING CONTINUATION	-$104,981
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	000	2	3/31/2022	NON-COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	004	2	4/28/2022	SUPPLEMENT FOR EXPANSION	-$400,912
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	001	2	3/31/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $367,692

Issue Date FY: 2021 ( Subtotal = $749,756 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	002	2	9/8/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	001	2	7/14/2021	SUPPLEMENT FOR EXPANSION	$400,912
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	000	2	1/29/2021	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $749,756

Issue Date FY: 2020 ( Subtotal = $348,844 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Treatment Research	000	1	2/10/2020	NEW	$348,844
														Subtotal = $348,844

Grand Total All Awards = $2,507,884

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The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC

Award Number: R37CA249305

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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