Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

被引：260

作者：

Sun, Chong ^{[1
]}

Hobor, Sebastijan ^{[2
]}

Bertotti, Andrea ^{[2
,3
]}

Zecchin, Davide ^{[2
,3
]}

Huang, Sidong ^{[1
,4
]}

Galimi, Francesco ^{[2
,3
]}

Cottino, Francesca ^{[2
]}

Prahallad, Anirudh ^{[1
]}

Grernrum, Wipawadee ^{[1
]}

Tzani, Anna ^{[1
]}

Schlicker, Andreas ^{[1
]}

Wessels, Lodewyk F. A. ^{[1
]}

Smit, Egbert F. ^{[5
]}

Thunnissen, Erik ^{[6
]}

Halonen, Pasi ^{[1
]}

Lieftink, Cor ^{[1
]}

Beijersbergen, Roderick L. ^{[1
]}

Di Nicolantonio, Federica ^{[3
]}

Bardelli, Alberto ^{[2
,3
,7
]}

Trusolino, Livio ^{[2
,3
]}

Bernards, Rene ^{[1
]}

机构：

[1] Netherlands Canc Inst, Canc Genom Ctr Netherlands, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[2] IRCCS, Candiolo Canc Inst FPO, I-10060 Turin, Italy

[3] Univ Turin, Dept Oncol, I-10060 Turin, Italy

[4] McGill Univ, Rosalind & Morris Goodman Canc Ctr, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[5] Vrije Univ Amsterdam, Med Ctr, Dept Pulm Dis, NL-1007 MB Amsterdam, Netherlands

[6] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands

[7] FIRC Inst Mol Oncol IFOM, I-20139 Milan, Italy

来源：

CELL REPORTS | 2014年 / 7卷 / 01期

基金：

欧洲研究理事会;

关键词：

MYC PROTEIN STABILITY; DRUG-SENSITIVITY; RAS ONCOGENES; C-MYC; KINASE; PHOSPHORYLATION; MELANOMA; RECEPTOR; BRAF; BAD;

D O I：

10.1016/j.celrep.2014.02.045

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

There are no effective therapies for the similar to 30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming hetero-dimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.

引用

页码：86 / 93

页数：8

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