PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.
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 1 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.
Max-Planck-Institute for Neurological Research with Klaus-Joachim Zülch Laboratories of the Max-Planck-Society and the Medical Faculty of the University of Köln, Germany.
Martin L
ML
Sos
Mirjam
M
Koker
Barbara A
BA
Weir
Stefanie
S
Heynck
Rosalia
R
Rabinovsky
Thomas
T
Zander
Jens M
JM
Seeger
Jonathan
J
Weiss
Florian
F
Fischer
Peter
P
Frommolt
Kathrin
K
Michel
Martin
M
Peifer
Craig
C
Mermel
Luc
L
Girard
Michael
M
Peyton
Adi F
AF
Gazdar
John D
JD
Minna
Levi A
LA
Garraway
Hamid
H
Kashkar
William
W
Pao
Matthew
M
Meyerson
Roman K
RK
Thomas
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human