Wednesday, September 17, 2025 9/17/2025

Rac guanine nucleotide exchange factors in lung cancer

Award Number: R01CA265999
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/31/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Rac guanine nucleotide exchange factors in lung cancer - ABSTRACT KRAS and EGFR mutations are the most prevalent genetic alterations detected in human lung adenocarcinomas, and play essential roles in malignant transformation and disease progression. The small GTPase Rac1, a member of the Rho family, is a key signaling effector of KRAS and EGFR oncogenic pathways. Rac1 has been widely implicated in the formation of actin-rich protrusive structures required for cancer cell motility and invasion, as well as in the activation of oncogenic and metastatic gene expression networks. Activation of Rac1 (i.e. GTP loading) is mediated by Rac-GEFs, a large family of Guanine nucleotide Exchange Factors largely associated with tumorigenesis and invasiveness. Strikingly, there is limited information on the contribution of Rac-GEFs to lung cancer progression. Moreover, their relationship to specific lung cancer oncogenic mutations remains unknown. We carried out a systematic and unbiased screening for Rac-GEFs responsible for driving pro-motile phenotypes in KRAS mutant NSCLC cell lines. This analysis unambiguously identified three Rac-GEFs (ARHGEF39, FARP1 and TIAM2) as mediators of ruffle formation and motility in NSCLC cells. To our surprise, well-studied GEFs, such as TIAM1, TRIO, VAV isoforms and P-REX isoforms, were either poorly expressed or dispensable in our model. We therefore hypothesize that these Rac-GEFs are major players in lung cancer progression. In Aim 1, we will generate KRAS mutant cell lines deficient in RacGEFs using a CRISPR/Cas9 approach, and determine their contribution to invasion, ECM protease production and metastasis in mouse models. In addition, the requirement of selected Rac-GEFs to the development of autochthonously-arising metastatic lung cancer will be determined using a lentiviral CRISPR-based gene editing approach in Kras G12D/WT; p53 flox/flox mice (KP mice). In Aim 2 the goal is to identify and characterize Rac-GEFs as EGFR effectors in NSCLC. To unequivocally elucidate their permissive roles in mutant EGFR lung cancer progression phenotypes, in vivo lentiviral CRISPR-based Rac-GEF gene editing in an EGFR L858R-driven, p53 deficient lung adenocarcinoma mouse model will be performed. Mechanistically, we aim to disentangle the basis of Rac-GEF activation by pursuing a comprehensive signaling analysis of proximal EGFR adaptors and effectors. In Aim 3, we will first elucidate Rac-GEF-dependent gene transcriptomes and network signatures driven by mutant KRAS and mutant EGFR. Finally, we will determine Rac-GEF expression in single tumor cells isolated from malignant pleural effusions (a site of lung metastatic dissemination), as well as in single and clustered circulating tumor cells (CTCs) from peripheral blood of mutant KRAS and mutant EGFR lung adenocarcinoma patients. The identification of novel Rac-GEFs provides unprecedented information to predict metastatic disease outcome in lung cancer patients and increase the likelihood of identifying metastasis biomarkers, ultimately aiding in refining patient prognosis and decision-making in a clinical setting.


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 = $934,459 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	002	4	9/10/2025	EXTENSION WITH OR WITHOUT FUNDS	$934,459
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	3	2/26/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$134,889
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	2/26/2025	NON-COMPETING CONTINUATION	-$134,889
														Subtotal = $934,459

Issue Date FY: 2024 ( Subtotal = $459,139 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	3	9/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$459,139
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	9/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,139

Issue Date FY: 2023 ( Subtotal = $461,082 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	7/28/2023	NON-COMPETING CONTINUATION	$461,082
														Subtotal = $461,082

Issue Date FY: 2022 ( Subtotal = $470,493 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	8/1/2022	NEW	$470,493
														Subtotal = $470,493

Grand Total All Awards = $2,325,173

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Rac guanine nucleotide exchange factors in lung cancer

Award Number: R01CA265999

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/31/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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