Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance

被引：326

作者：

Marcotte, Richard ^{[1
]}

Sayad, Azin ^{[1
]}

Brown, Kevin R. ^{[2
]}

Sanchez-Garcia, Felix ^{[4
]}

Reimand, Jueri ^{[2
]}

Haider, Maliha ^{[1
]}

Virtanen, Carl ^{[1
]}

Bradner, James E. ^{[5
,6
]}

Bader, Gary D. ^{[2
]}

Mills, Gordon B. ^{[7
]}

Pe'er, Dana ^{[4
]}

Moffat, Jason ^{[2
,3
]}

Neel, Benjamin G. ^{[1
,8
]}

机构：

[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[2] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[3] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada

[4] Columbia Univ, New York, NY 10027 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[6] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA

[7] Univ Texas MD Anderson Canc Ctr, Sheikh Khalifa Al Nahyan Ben Zayed Inst Personali, Dept Syst Biol, Houston, TX 77030 USA

[8] NYU Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA

来源：

CELL | 2016年 / 164卷 / 1-2期

关键词：

CELL-LINES; DUAL INHIBITION; REVEALS; GROWTH; KINASE; ATM; PHOSPHORYLATION; SUPPRESSION; PATTERNS; SUBTYPE;

D O I：

10.1016/j.cell.2015.11.062

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：

Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole-genome small hairpin RNA (shRNA) "dropout screens" on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate "drivers," and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer and PIK3CA mutations as a resistance determinant for BET-inhibitors.

引用

页码：293 / 309

页数：17

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