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.
Sos
Martin L
ML
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.
Koker
Mirjam
M
Weir
Barbara A
BA
Heynck
Stefanie
S
Rabinovsky
Rosalia
R
Zander
Thomas
T
Seeger
Jens M
JM
Weiss
Jonathan
J
Fischer
Florian
F
Frommolt
Peter
P
Michel
Kathrin
K
Peifer
Martin
M
Mermel
Craig
C
Girard
Luc
L
Peyton
Michael
M
Gazdar
Adi F
AF
Minna
John D
JD
Garraway
Levi A
LA
Kashkar
Hamid
H
Pao
William
W
Meyerson
Matthew
M
Thomas
Roman K
RK
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