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

Year: 2015 2014 2013 2012 2011 2010 Total
Citations: 8 34 43 28 28 2 143
Citation information

Citations to this article (143)

Title and authors Publication Year
The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges
B Cheaib, A Auguste, A Leary
Chinese journal of cancer 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
Current treatment strategies for inhibiting mTOR in cancer
F Chiarini, C Evangelisti, JA McCubrey, AM Martelli
Trends in Pharmacological Sciences 2015
Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing
S Liu, H Wang, L Zhang, C Tang, L Jones, H Ye, L Ban, A Wang, Z Liu, F Lou, D Zhang, H Sun, H Dong, G Zhang, Z Dong, B Guo, H Yan, C Yan, L Wang, Z Su, Y Li, XF Huang, SY Chen, T Zhou
Human genomics 2015
CCI-779 (Temsirolimus) exhibits increased anti-tumor activity in low EGFR expressing HNSCC cell lines and is effective in cells with acquired resistance to cisplatin or cetuximab
F Niehr, W Weichert, A Stenzinger, V Budach, I Tinhofer
Journal of Translational Medicine 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
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
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
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
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
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
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
Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment
H Cheng, M Shcherba, G Pendurti, Y Liang, B Piperdi, R Perez-Soler
Lung Cancer Management 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
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
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, J Pratap
PloS one 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
Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials
Rabih Said, Yang Ye, Gerald Steven Falchook, Filip Janku, Aung Naing, Ralph Zinner, George R. Blumenschein Jr., Siqing Fu, David S. Hong, Sarina Anne Piha-Paul, Jennifer J. Wheler, Razelle Kurzrock, Gary A. Palmer, Kenneth Aldape, Kenneth R. Hess, Apostolia Maria Tsimberidou
Oncotarget 2014

Advertisement
Advertisement