Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition

被引：1

作者：

Rowdo, Florencia P. Madorsky ^{[1
]}

Martini, Rachel ^{[2
,3
]}

Ackermann, Sarah E. ^{[1
]}

Tang, Colin P. ^{[4
]}

Tranquille, Marvel ^{[1
]}

Irizarry, Adriana ^{[1
]}

Us, Ilkay ^{[1
]}

Alawa, Omar ^{[1
]}

Moyer, Jenna E. ^{[1
]}

Sigouros, Michael ^{[1
]}

Nguyen, John ^{[1
]}

Al Assaad, Majd ^{[1
,5
]}

Cheng, Esther ^{[5
]}

Ginter, Paula S. ^{[6
]}

Manohar, Jyothi ^{[1
]}

Stonaker, Brian ^{[2
]}

Boateng, Richard ^{[7
]}

Oppong, Joseph K. ^{[7
]}

Adjei, Ernest K. ^{[7
]}

Awuah, Baffour ^{[7
]}

Kyei, Ishmael ^{[8
]}

Aitpillah, Francis S. ^{[7
]}

Adinku, Michael O. ^{[8
]}

Ankomah, Kwasi ^{[7
]}

Osei-Bonsu, Ernest B. ^{[7
]}

Gyan, Kofi K. ^{[2
]}

Hoda, Syed ^{[5
]}

Newman, Lisa ^{[2
]}

Mosquera, Juan Miguel ^{[1
,5
]}

Sboner, Andrea ^{[1
,4
]}

Elemento, Olivier ^{[1
,4
]}

Dow, Lukas E. ^{[9
,10
,11
]}

Davis, Melissa B. ^{[1
,2
,3
]}

Martin, M. Laura ^{[1
]}

机构：

[1] Weill Cornell Med, Englander Inst Precis Med, 413 E 69th St,R1450, New York, NY 10021 USA

[2] Weill Cornell Med, Dept Surg, New York, NY 10021 USA

[3] Morehouse Sch Med, Inst Translat Genom Med, 720 Westview Dr, Atlanta, GA 30410 USA

[4] Weill Cornell Med, Inst Computat Biomed, Dept Physiol & Biophys, New York, NY 10021 USA

[5] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10021 USA

[6] NYU, Langone Hosp Long Isl, Dept Pathol, Mineola, NY USA

[7] Komfo Anokye Teaching Hosp, Kumasi, Ghana

[8] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana

[9] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10021 USA

[10] Weill Cornell Med Coll, Dept Med, New York, NY USA

[11] New York Presbyterian Hosp, New York, NY USA

来源：

CANCER RESEARCH | 2025年 / 85卷 / 03期

关键词：

PHASE-II; IN-VITRO; OPPORTUNITIES; COMBINATION; CHALLENGES; GEFITINIB; RESISTANT; TARGETS; BIOLOGY; WOMEN;

D O I：

10.1158/0008-5472.CAN-24-0775

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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

引用

页码：551 / 566

页数：16