Citations to this article


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.


Federica Di Nicolantonio ... Stefano Biffo, Alberto Bardelli


Total citations by year

Year: 2014 2013 2012 2011 2010 Total
Citations: 31 41 28 28 2 130
Citation information

Citations to this article (130)

Title and authors Publication Year
Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors
F Janku, DS Hong, S Fu, SA Piha-Paul, A Naing, GS Falchook, AM Tsimberidou, VM Stepanek, SL Moulder, JJ Lee, R Luthra, RG Zinner, RR Broaddus, JJ Wheler, R Kurzrock
Cell Reports 2014
Targeting the mTOR pathway in hepatocellular carcinoma: Current state and future trends
MS Matter, T Decaens, JB Andersen, SS Thorgeirsson
Journal of Hepatology 2014
A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: A Gynecologic Oncology Group study
SM Campos, WE Brady, KM Moxley, RE O'Cearbhaill, PS Lee, PA DiSilvestro, J Rotmensch, PG Rose, PH Thaker, DM O'Malley, P Hanjani, RE Zuna, ML Hensley
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
Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies
SM Leto, L Trusolino
Journal of Molecular Medicine 2014
PI3K/AKT signaling pathway and cancer: an updated review
M Martini, MC de Santis, L Braccini, F Gulluni, E Hirsch
Annals of Medicine 2014
The Search Continues: Looking for Predictive Biomarkers for Response to Mammalian Target of Rapamycin Inhibition in Endometrial Cancer
LA Meyer, BM Slomovitz, B Djordjevic, SN Westin, DA Iglesias, MF Munsell, Y Jiang, R Schmandt, RR Broaddus, RL Coleman, JM Galbincea, KH Lu
International Journal of Gynecological Cancer 2014
PIK3CA Mutations in Mucinous Cystic Neoplasms of the Pancreas:
D Garcia-Carracedo, ZM Chen, W Qiu, AS Huang, SM Tang, RH Hruban, GH Su
Pancreas 2014
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway
J Polivka, F Janku
Pharmacology & Therapeutics 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
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
Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow
G Deng, S Krishnakumar, AA Powell, H Zhang, MN Mindrinos, ML Telli, RW Davis, SS Jeffrey
BMC Cancer 2014
Targeting mTOR network in colorectal cancer therapy
XW Wang, YJ Zhang
World journal of gastroenterology : WJG 2014
FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors
DL Jardim, JJ Wheler, K Hess, AM Tsimberidou, R Zinner, F Janku, V Subbiah, A Naing, SA Piha-Paul, SN Westin, S Roy-Chowdhuri, F Meric-Bernstam, DS Hong
PloS one 2014
Activity of EGFR, mTOR and PI3K inhibitors in an isogenic breast cell line model
S Glaysher, LM Bolton, P Johnson, C Torrance, IA Cree
BMC Research Notes 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
A comparative analysis of constitutive promoters located in adeno-associated viral vectors
L Damdindorj, S Karnan, A Ota, E Hossain, Y Konishi, Y Hosokawa, H Konishi
PloS one 2014
The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers
E Paplomata, R O'Regan
Therapeutic advances in medical oncology 2014
The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers
E Paplomata, R O’Regan
Therapeutic advances in medical oncology 2014
Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy
MH Voss, AA Hakimi, CG Pham, AR Brannon, YB Chen, LF Cunha, O Akin, H Liu, S Takeda, SN Scott, ND Socci, A Viale, N Schultz, C Sander, VE Reuter, P Russo, EH Cheng, RJ Motzer, MF Berger, JJ Hsieh
Clinical cancer research : an official journal of the American Association for Cancer Research 2014
Implementation of biomarker-driven cancer therapy: existing tools and remaining gaps
AM Bailey, Y Mao, J Zeng, V Holla, A Johnson, L Brusco, K Chen, J Mendelsohn, MJ Routbort, GB Mills, F Meric-Bernstam
Discovery medicine 2014
In vitro and in vivo models for analysis of resistance to anticancer molecular therapies
R Rosa, F Monteleone, N Zambrano, R Bianco
Current medicinal chemistry 2014
In Vitro and In Vivo Models for Analysis of Resistance to Anticancer Molecular Therapies
R Rosa, F Monteleone, N Zambrano, R Bianco
Current medicinal chemistry 2014