title: Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations.
abstract: Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Takeuchi
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Oda
authors.forename: T
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Y
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Y
authors.initials: Y
authors.lastname: Sekido
authors.forename: J
authors.initials: J
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Higashiyama
authors.forename: M
authors.initials: M
authors.lastname: Noguchi
authors.forename: H
authors.initials: H
authors.lastname: Uehara
authors.forename: Y
authors.initials: Y
authors.lastname: Nishioka
authors.forename: S
authors.initials: S
authors.lastname: Sone
authors.forename: S
authors.initials: S
authors.lastname: Yano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: C512283:CC2D1A protein, human; D004268:DNA-Binding Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors