Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition
Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407.
Authors
- Brian Stonaker (ORCID: https://orcid.org/0000-0002-9567-0052)
- Michael O. Adinku (ORCID: https://orcid.org/0000-0003-0896-3189)
- Ernest Osei‐Bonsu (ORCID: https://orcid.org/0000-0002-3657-3519)
- Esther Cheng (ORCID: https://orcid.org/0009-0007-1812-5265)
- Jenna E. Moyer (ORCID: https://orcid.org/0000-0002-4599-2969)
- Jyothi Manohar (ORCID: https://orcid.org/0000-0001-6357-910X)
- Paula S. Ginter (ORCID: https://orcid.org/0000-0002-5107-5411)
- Joseph K. Oppong (ORCID: https://orcid.org/0000-0003-2455-2734)
- Ilkay Us
- Colin P. Tang (ORCID: https://orcid.org/0000-0001-9361-8085)
- Lisa A. Newman (ORCID: https://orcid.org/0000-0003-2059-0477)
- Majd Al Assaad (ORCID: https://orcid.org/0000-0002-9512-0253)
- Syed A. Hoda (ORCID: https://orcid.org/0000-0002-1478-5115)
- Lukas E. Dow (ORCID: https://orcid.org/0000-0001-7048-1418)
- Ernest Adjei (ORCID: https://orcid.org/0000-0002-4004-3334)
- Baffour Awuah (ORCID: https://orcid.org/0000-0002-2371-1695)
- Michael Sigouros (ORCID: https://orcid.org/0000-0002-0328-8359)
- Florencia P. Madorsky Rowdo (ORCID: https://orcid.org/0000-0002-8504-1690)
- Rachel Martini (ORCID: https://orcid.org/0000-0002-8921-0041)
- Kwasi Ankomah (ORCID: https://orcid.org/0000-0003-1290-8406)
- Adriana Irizarry
- M. Laura Martín (ORCID: https://orcid.org/0000-0001-9359-5856)
- Sarah E. Ackermann (ORCID: https://orcid.org/0000-0002-6898-7361)
- Kofi K. Gyan (ORCID: https://orcid.org/0000-0003-1281-2164)
- Richard Boateng (ORCID: https://orcid.org/0000-0003-3599-9136)
- John Nguyen (ORCID: https://orcid.org/0009-0007-0560-6684)
- Juan Miguel Mosquera (ORCID: https://orcid.org/0000-0003-4666-6476)
- Andrea Sboner (ORCID: https://orcid.org/0000-0001-6915-3070)
- Melissa B. Davis (ORCID: https://orcid.org/0000-0002-6124-6923)
- Ishmael Kyei (ORCID: https://orcid.org/0000-0002-8419-8637)
- Olivier Elemento (ORCID: https://orcid.org/0000-0002-8061-9617)
- Marvel Tranquille (ORCID: https://orcid.org/0000-0002-6608-5778)
- Francis Aitpillah (ORCID: https://orcid.org/0000-0001-9495-6887)
- Omar Alawa (ORCID: https://orcid.org/0009-0000-5882-2961)
Institutions
- Cornell University (US)
- Komfo Anokye Teaching Hospital (GH)
- Kwame Nkrumah University of Science and Technology (GH)
- Lander Institute (IL)
- Presbyterian Hospital (US)
- Island Hospital (US)
- Morehouse School of Medicine (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1158/0008-5472.can-24-0775
- Citations
- 10
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- Breast Cancer Research Foundation
- National Institutes of Health
- Weill Cornell Medical College
- Weill Cornell Medicine
- National Cancer Institute