Advertisement

Citations to this article

Abstract

Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors.

Authors

Federica Di Nicolantonio ... Stefano Biffo, Alberto Bardelli

×

Total citations by year in Crossref

Year: 2015 2014 2013 2012 2011 Total
Citations: 5 14 17 11 13 60
Citation information

Citations to this article in Crossref (60)

Title and authors Publication Year
Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer
E Deutsch, CL Pechoux, L Faivre, S Rivera, Y Tao, JP Pignon, M Angokai, R Bahleda, D Deandreis, E Angevin, C Hennequin, B Besse, A Levy, JC Soria
Annals of Oncology 2015
Toward precision medicine in glioblastoma: the promise and the challenges
MD Prados, SA Byron, NL Tran, JJ Phillips, AM Molinaro, KL Ligon, PY Wen, JG Kuhn, IK Mellinghoff, JF de Groot, H Colman, TF Cloughesy, SM Chang, TC Ryken, WD Tembe, JA Kiefer, ME Berens, DW Craig, JD Carpten, JM Trent
Neuro-Oncology 2015
Current treatment strategies for inhibiting mTOR in cancer
F Chiarini, C Evangelisti, JA McCubrey, AM Martelli
Trends in Pharmacological Sciences 2015
PIKing the type and pattern of PI3K pathway mutations in endometrioid endometrial carcinomas
C Marchiò, MR de Filippo, CK Ng, S Piscuoglio, RA Soslow, JS Reis-Filho, B Weigelt
Gynecologic Oncology 2015
Molecular histology of lung cancer: From targets to treatments
SL Wood, M Pernemalm, PA Crosbie, AD Whetton
Cancer Treatment Reviews 2015
PI3K/AKT signaling pathway and cancer: an updated review
M Martini, MC de Santis, L Braccini, F Gulluni, E Hirsch
Annals of Medicine 2014
Predictive biomarker candidates for the response of gastric cancer to targeted and cytotoxic agents
HK Kim, JE Green
Pharmacogenomics 2014
Precision medicine for metastatic renal cell carcinoma
G Sonpavde, TK Choueiri
Urologic Oncology: Seminars and Original Investigations 2014
mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: A critical review
N Husseinzadeh, HD Husseinzadeh
Gynecologic Oncology 2014
Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single-arm, phase 2 study
M Wang, LL Popplewell, RH Collins, JN Winter, A Goy, MS Kaminski, NL Bartlett, PB Johnston, J Lister, SR Fanning, JM Tuscano, JT Beck, H Kaya, A Robeva, J Fan, J Klimovsky, W Cheung, A Cherfi, OA O'Connor
British Journal of Haematology 2014
Analysis of Molecular Cytogenetic Changes in Metastatic Renal Cell Carcinoma in the Setting of Everolimus Treatment: A Pilot Project
IR Caldwell, P Oei, D Ng, B Caudwell, PC Fong, RJ Broom
Clinical Genitourinary Cancer 2014
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway
J Polivka, F Janku
Pharmacology & Therapeutics 2014
Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics
R Horii, M Matsuura, S Dan, M Ushijima, N Uehiro, A Ogiya, N Honma, Y Ito, T Iwase, T Yamori, F Akiyama
International Journal of Clinical Oncology 2014
Dual Inhibition of Phosphatidylinositol 3′-Kinase and Mammalian Target of Rapamycin Using NVP-BEZ235 as a Novel Therapeutic Approach for Mucinous Adenocarcinoma of the Ovary:
A Kudoh, T Oishi, H Itamochi, S Sato, J Naniwa, S Sato, M Shimada, J Kigawa, T Harada
International Journal of Gynecological Cancer 2014
LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo
J Zhou, B Zheng, J Ji, F Shen, H Min, B Liu, J Wu, S Zhang
Tumor Biology 2014
Treatment of ovarian cancer beyond chemotherapy: Are we hitting the target?
ÁH Garces, MS Dias, E Paulino, CG Ferreira, AC de Melo
Cancer Chemotherapy and Pharmacology 2014
Molecular spectrum of KRAS, BRAF, and PIK3CA gene mutation: determination of frequency, distribution pattern in Indian colorectal carcinoma
S Bisht, F Ahmad, S Sawaimoon, S Bhatia, BR Das
Medical Oncology 2014
MicroRNA and signaling pathways in gastric cancer
Z Zhang, Z Li, Y Li, A Zang
Cancer Gene Therapy 2014
Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors
J Rodon, I Braña, LL Siu, MJ Jonge, N Homji, D Mills, E Tomaso, C Sarr, L Trandafir, C Massacesi, F Eskens, JC Bendell
Investigational New Drugs 2014
Patterns of DNA Mutations and ALK Rearrangement in Resected Node Negative Lung Adenocarcinoma:
PY Yip, B Yu, WA Cooper, CI Selinger, CC Ng, CW Kennedy, MR Kohonen-Corish, BC McCaughan, RJ Trent, MJ Boyer, JG Kench, LG Horvath, SA O’Toole
Journal of Thoracic Oncology 2013
Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model
K Harada, H Miyake, Y Kusuda, M Fujisawa
Clinical and Translational Oncology 2013
Translation factors and ribosomal proteins control tumor onset and progression: how?
F Loreni, M Mancino, S Biffo
Oncogene 2013
Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer
KS Saini, S Loi, E Azambuja, O Metzger-Filho, ML Saini, M Ignatiadis, JE Dancey, MJ Piccart-Gebhart
Cancer Treatment Reviews 2013
Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma: Combined Targeting of AKT and mTOR for CCA
F Ewald, N Grabinski, A Grottke, S Windhorst, D Nörz, L Carstensen, K Staufer, BT Hofmann, F Diehl, K David, U Schumacher, B Nashan, M Jücker
International Journal of Cancer 2013
The potential role of new targeted therapies in the treatment of advanced non-small-cell lung cancer
F Casaluce, A Sgambato, P Maione, A Rossi, C Ferrara, A Napolitano, G Palazzolo, F Ciardiello, C Gridelli
Clinical Investigation 2013

Advertisement
Advertisement