title: Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.
abstract: Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance.
authors: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors: Keisuke
authors: K
authors: Tabara
authors: Rina
authors: R
authors: Kanda
authors: Kahori
authors: K
authors: Sonoda
authors: Takuya
authors: T
authors: Kubo
authors: Yuichi
authors: Y
authors: Murakami
authors: Akihiko
authors: A
authors: Kawahara
authors: Koichi
authors: K
authors: Azuma
authors: Hideyuki
authors: H
authors: Abe
authors: Masayoshi
authors: M
authors: Kage
authors: Aki
authors: A
authors: Yoshinaga
authors: Tomoko
authors: T
authors: Tahira
authors: Kenshi
authors: K
authors: Hayashi
authors: Tokuzo
authors: T
authors: Arao
authors: Kazuto
authors: K
authors: Nishio
authors: Rafael
authors: R
authors: Rosell
authors: Michihiko
authors: M
authors: Kuwano
authors: Mayumi
authors: M
authors: Ono
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib