Genome-wide in vivo CRISPR screen identifies TGFβ3 as actionable biomarker of palbociclib resistance in triple negative breast cancer

被引：6

作者：

Poulet, Sophie ^{[1
]}

Dai, Meiou ^{[1
]}

Wang, Ni ^{[1
]}

Yan, Gang ^{[1
]}

Boudreault, Julien ^{[1
]}

Daliah, Girija ^{[1
]}

Guillevin, Alan ^{[1
]}

Nguyen, Huong ^{[1
]}

Galal, Soaad ^{[1
]}

Ali, Suhad ^{[1
]}

Lebrun, Jean-Jacques ^{[1
]}

机构：

[1] McGill Univ, Dept Med, Hlth Ctr, Canc Res Program, Montreal, PQ, Canada

来源：

MOLECULAR CANCER | 2024年 / 23卷 / 01期

关键词：

PROMOTES RB DEGRADATION; UBIQUITIN LIGASE; CDK INHIBITORS; CELL-LINES; ESTROGEN; INVOLUTION; EXPRESSION; GENES; MODEL;

D O I：

10.1186/s12943-024-02029-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGF beta 3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGF beta 3 treatment can overcome this. This study defines TGF beta 3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGF beta 3 to propose a new combinatorial treatment for TNBC.

引用

页数：21

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