Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.
Kirstine Jacobsen,Jordi Bertran-Alamillo,Miguel Angel Molina,Cristina Teixidó,Niki Karachaliou,Martin Haar Pedersen,Josep Castellví,Mónica Garzón,Carles Codony-Servat,Jordi Codony-Servat,Ana Giménez-Capitán,Ana Drozdowskyj,Santiago Viteri,Martin R. Larsen,Ulrik Lassen,Enriqueta Felip,Trever G. Bivona,Henrik J. Ditzel,Henrik J. Ditzel,Rafael Rosell +19 more
TLDR
It is shown that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.Abstract:
Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms. EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.read more
Citations
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Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations
Lecia V. Sequist,James Chih-Hsin Yang,Nobuyuki Yamamoto,Kenneth J. O'Byrne,Vera Hirsh,Tony Mok,Sarayut Lucien Geater,Sergey Orlov,Chun-Ming Tsai,Michael Boyer,Wu Chou Su,Jaafar Bennouna,Terufumi Kato,Vera Gorbunova,Ki Hyeong Lee,Riyaz Shah,Dan Massey,Victoria Zazulina,Mehdi Shahidi,Martin Schuler +19 more
TL;DR: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Journal ArticleDOI
AKt as a therapeutic target for cancer
TL;DR: The abnormal overexpression or activation of AKT has been observed in many cancers, including ovarian, lung, and pancreatic cancers, and is associated with increased cancer cell proliferation and survival, so targeting AKT could provide an important approach for cancer prevention and therapy.
Journal ArticleDOI
Advances in studies of tyrosine kinase inhibitors and their acquired resistance
TL;DR: The role of PTK in cancer, TKI treatment of tumor pathways and TKI acquired resistance mechanisms are summarized to provide some reference for further research on TKIs treatment of tumors.
References
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Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
Jacques Ferlay,Isabelle Soerjomataram,Rajesh Dikshit,Sultan Eser,Colin Mathers,Marise Souto Rebelo,Donald Maxwell Parkin,David Forman,Freddie Bray +8 more
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
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Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Makoto Maemondo,Akira Inoue,Kunihiko Kobayashi,Shunichi Sugawara,Satoshi Oizumi,Hiroshi Isobe,Akihiko Gemma,Masao Harada,Hirohisa Yoshizawa,Ichiro Kinoshita,Yuka Fujita,Shoji Okinaga,Haruto Hirano,Kozo Yoshimori,Toshiyuki Harada,Takashi Ogura,Masahiro Ando,Hitoshi Miyazawa,Tomoaki Tanaka,Yasuo Saijo,Koichi Hagiwara,Satoshi Morita,Toshihiro Nukiwa +22 more
TL;DR: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy.
Journal ArticleDOI
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Rafael Rosell,Enric Carcereny,Radj Gervais,A. Vergnenegre,Bartomeu Massuti,Enriqueta Felip,Ramon Palmero,Ramon Garcia-Gomez,Cinta Pallares,Jose Miguel Sanchez,Rut Porta,Manuel Cobo,Pilar Garrido,Flavia Longo,Teresa Moran,A. Insa,Filippo de Marinis,Romain Corre,Isabel Bover,Alfonso Illiano,Eric Dansin,Javier de Castro,Michele Milella,Noemi Reguart,Giuseppe Altavilla,Ulpiano Jimenez,Mariano Provencio,Miguel Angel Moreno,J. Terrasa,Jose Muñoz-Langa,Javier Valdivia,Dolores Isla,Manuel Domine,Olivier Molinier,Julien Mazieres,Nathalie Baize,Rosario García-Campelo,Gilles Robinet,Delvys Rodriguez-Abreu,Guillermo Lopez-Vivanco,Vittorio Gebbia,Lioba Ferrera-Delgado,Pierre Bombaron,R. Bernabé,Alessandra Bearz,Angel Artal,Enrico Cortesi,Christian Rolfo,Maria Sanchez-Ronco,Ana Drozdowskyj,Cristina Queralt,Itziar de Aguirre,Jose Luis Ramirez,Jose Javier Sanchez,Miguel Angel Molina,Miquel Taron,Luis Paz-Ares +56 more
TL;DR: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations as discussed by the authors.
Journal ArticleDOI
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Susumu Kobayashi,Titus J. Boggon,Tajhal Dayaram,Pasi A. Jänne,Olivier Kocher,Matthew Meyerson,Bruce E. Johnson,Michael J. Eck,Daniel G. Tenen,Balazs Halmos,Balazs Halmos +10 more
TL;DR: In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.
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Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
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