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Understanding the molecular mechanism of a protein-recycling complex in small cell lung cancer treatment resistance.

Award Number: U01CA253383
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Small cell lung cancer (SCLC) patients have an initial robust response to combinations of DNA damaging agents (e.g. cisplatin, etoposide, radiotherapy), however, many patients inevitably suffer from relapse and resistant disease. A clear understanding of these resistance mechanisms remains elusive. Consequently, there is a critical need to: (1) understand the mechanisms of therapeutic resistance and (2) develop novel therapeutics. Poly-(ADP)-ribose polymerase enzymes (PARP) protein levels are upregulated in SCLC relative to other lung cancers, and initial studies suggest that this upregulation is associated with increased sensitivity of SCLC to PARP inhibitors (PARPi) in vitro. PARP inhibitors are synthetic lethal with BRCA1/2 mutated homologous recombination (HR) deficient tumors and restoration of HR by BRCA reversion mutations is a known mechanism of PARPi and cisplatin resistance. However, as BRCA1/2 mutations are exceedingly rare in SCLC non-BRCA mechanisms must be operant. We performed a genome-wide CRISPR knockout screen to identify novel mechanisms of PARPi resistance. From subsequent functional validation and clinical genomic correlation, we identified deficiency in an F-box protein coding gene as a putative biomarker of resistance to PARP inhibitors and cisplatin in SCLC that may be present in up to ~20% of relapse patient tumors. Loss of this F-box protein abrogates the function of its corresponding SKP1, CUL1, F-box (SCF) E3 ubiquitin ligase complex. By proximity-dependent biotin identification (BioID) of this F-box protein, we have identified a high confidence interactor with substrate-like behavior for SCF-mediated ubiquitin-proteasomal degradation that is important for regulation of HR and DNA repair. This proposal aims to: (1) determine the mechanism of this specific SCF complex with its substrate to engage the ubiquitin-proteasome pathway; (2) elucidate the impact of this F-box protein on HR, DNA repair, and therapeutic sensitivity to PARPi/cisplatin; and (3) identify synthetic lethal interactions with deficiencies in this F-box protein to provide biologic insight and characterize immediately translatable approaches for relapsed treatment resistant SCLC.


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: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Cause and Prevention Research	000	3	12/21/2022	NON-COMPETING CONTINUATION	$0
2023	2022	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Cause and Prevention Research	001	3	4/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $333,379 )
2022	2022	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Cause and Prevention Research	000	3	8/15/2022	NON-COMPETING CONTINUATION	$333,379
														Subtotal = $333,379

Issue Date FY: 2021 ( Subtotal = $295,362 )
2021	2021	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Cause and Prevention Research	000	2	8/10/2021	NON-COMPETING CONTINUATION	$295,362
														Subtotal = $295,362

Issue Date FY: 2020 ( Subtotal = $281,916 )
2020	2020	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Cause and Prevention Research	000	1	9/25/2020	NEW	$281,916
														Subtotal = $281,916

Grand Total All Awards = $910,657

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Understanding the molecular mechanism of a protein-recycling complex in small cell lung cancer treatment resistance.

Award Number: U01CA253383

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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