PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR

被引：431

作者：

Sos, Martin L. ^{[13
,14
]}

Koker, Miriam ^{[13
,14
]}

Weir, Barbara A. ^{[9
,10
]}

Heynck, Stefanie ^{[13
,14
]}

Rabinovsky, Rosalia ^{[8
]}

Zander, Thomas ^{[15
,16
]}

Seeger, Jens M. ^{[12
]}

Weiss, Jonathan ^{[13
,14
]}

Fischer, Florian ^{[13
,14
]}

Frommolt, Peter ^{[11
]}

Michel, Kathrin ^{[13
,14
]}

Peifer, Martin ^{[13
,14
]}

Mermel, Craig ^{[8
,9
,10
]}

Girard, Luc ^{[5
]}

Peyton, Michael ^{[5
]}

Gazdar, Adi F. ^{[4
,5
]}

Minna, John D. ^{[3
,5
]}

Garraway, Levi A. ^{[7
,8
,9
,10
]}

Kashkar, Hamid ^{[12
]}

Pao, William ^{[2
]}

Meyerson, Matthew ^{[6
,7
,8
,9
,10
]}

Thomas, Roman K. ^{[1
,13
,14
,15
,16
]}

机构：

[1] Max Planck Gesell, Chem Genom Ctr, Dortmund, Germany

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Internal Med & Pharmacol, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA

[9] Broad Inst Harvard, Cambridge, MA USA

[10] MIT, Cambridge, MA 02139 USA

[11] Inst Med Stat Informat & Epidemiol, Cologne, Germany

[12] Inst Med Microbiol Immunol & Hyg, Cologne, Germany

[13] Max Planck Gesell, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany

[14] Univ Cologne, Fac Med, Cologne, Germany

[15] Univ Cologne, Ctr Integrated Oncol, Cologne, Germany

[16] Univ Cologne, Dept Internal Med 1, Cologne, Germany

来源：

CANCER RESEARCH | 2009年 / 69卷 / 08期

基金：

芬兰科学院;

关键词：

ACQUIRED-RESISTANCE; KINASE INHIBITORS; SENSITIVITY; MUTATIONS; SURVIVAL; EXPRESSION; GEFITINIB; PATHWAYS; BIM;

D O I：

10.1158/0008-5472.CAN-08-4055

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in I out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. [Cancer Res 2009;69(8):3256-61]

引用

页码：3256 / 3261

页数：6

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