2. Academic Validation
  3. Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies

Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies

  • Cancer Discov. 2025 Aug 12. doi: 10.1158/2159-8290.CD-25-0299.
Pu Zhang 1,  Zhendong Cao 2,  Xiangyu Pan 3,  Yuqiao Liu 4,  Cynthia Castro 5,  Won Jun Kim 5,  Takeshi Fujino 6,  Jennifer Lewis 5,  Jahan Rahman 6,  Sanam Shahid 7,  Jasmine Um 5,  Erin Burns 5,  Bingyi Chen 1,  Winson Cai 6,  Juliana Ortiz-Pacheco 5,  Zhuoning Li 7,  Mara Monetti 5,  Christopher R Vakoc 8,  Anthony F Daniyan 6,  Omar Abdel-Wahab 5,  Junwei Shi 4
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, United States.
  • 2 MSKCC, New York, NY, United States.
  • 3 Weill Cornell Medicine, United States.
  • 4 University of Pennsylvania, Philadelphia, PA, United States.
  • 5 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 6 Memorial Sloan Kettering Cancer Center, New York, New York, United States.
  • 7 Memorial Sloan Kettering Cancer Center, New York, United States.
  • 8 Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
PMID: 40788260 DOI: 10.1158/2159-8290.CD-25-0299
Abstract

GAPs (GTPase-activating proteins) and GEFs (guanine nucleotide exchange factors) play key roles in Cancer development, but their large number and potential redundancy have limited systematic evaluation. Here we perform unbiased genetic screens to identify GAPs and GEFs with cancer- and lineage-specific requirements, as well as dual perturbation screens to dissect functionally relevant interactors of GAPs and GEFs. Application to primary acute myeloid leukemia (AML) patient specimens uncovers the GAP ARHGAP45 as a targetable dependency shared across cancers of hematopoietic origin while being dispensable in normal hematopoiesis. We demonstrate that targeting ARHGAP45-expressing cells can be achieved through TCR-CAR T cells directed at an ARHGAP45-encoded minor histocompatibility antigen and that pharmacologic targeting of GAPs required upon ARHGAP45 depletion augments ARHGAP45-directed cell therapies. These studies provide a resource for probing oncogenic and druggable regulators of GTPases and strategies to target a GAP that represents a shared dependency across blood cancers.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112842
    99.64%, Rac/Cdc42 Inhibitor
    Ras; CDK