Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

被引：242

作者：

Janku, Filip ^{[1
]}

Hong, David S. ^{[1
]}

Fu, Siqing ^{[1
]}

Piha-Paul, Sarina A. ^{[1
]}

Naing, Aung ^{[1
]}

Falchook, Gerald S. ^{[1
]}

Tsimberidou, Apostolia M. ^{[1
]}

Stepanek, Vanda M. ^{[1
]}

Moulder, Stacy L. ^{[1
]}

Lee, J. Jack ^{[2
]}

Luthra, Rajyalakshmi ^{[3
]}

Zinner, Ralph G. ^{[1
]}

Broaddus, Russell R. ^{[4
]}

Wheler, Jennifer J. ^{[1
]}

Kurzrock, Razelle ^{[5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Phase Clin Trials Program 1, Dept Invest Canc Therapeut, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Mol Diagnost Lab, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[5] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

来源：

CELL REPORTS | 2014年 / 6卷 / 02期

关键词：

I CLINICAL-TRIALS; SOLID TUMORS; KINASE INHIBITORS; TYROSINE KINASE; MEK INHIBITORS; HIGH-FREQUENCY; MUTATIONS; CANCER; PI3K; RESISTANCE;

D O I：

10.1016/j.celrep.2013.12.035

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease >= 6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

引用

页码：377 / 387

页数：11

共 39 条

[1]

Cancer-specific mutations in PIK3CA are oncogenic in vivo [J].

Bader, AG ;

Kang, SY ;

Vogt, PK .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (05) :1475-1479

[2]

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [J].

Bang, Yung-Jue ;

Van Cutsem, Eric ;

Feyereislova, Andrea ;

Chung, Hyun C. ;

Shen, Lin ;

Sawaki, Akira ;

Lordick, Florian ;

Ohtsu, Atsushi ;

Omuro, Yasushi ;

Satoh, Taroh ;

Aprile, Giuseppe ;

Kulikov, Evgeny ;

Hill, Julie ;

Lehle, Michaela ;

Ruschoff, Josef ;

Kang, Yoon-Koo .

LANCET, 2010, 376 (9742) :687-697

[3]

High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability [J].

Cheung, Lydia W. T. ;

Hennessy, Bryan T. ;

Li, Jie ;

Yu, Shuangxing ;

Myers, Andrea P. ;

Djordjevic, Bojana ;

Lu, Yiling ;

Stemke-Hale, Katherine ;

Dyer, Mary D. ;

Zhang, Fan ;

Ju, Zhenlin ;

Cantley, Lewis C. ;

Scherer, Steven E. ;

Liang, Han ;

Lu, Karen H. ;

Broaddus, Russell R. ;

Mills, Gordon B. .

CANCER DISCOVERY, 2011, 1 (02) :170-185

[4]

COX DR, 1972, J R STAT SOC B, V34, P187

[5]

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis [J].

De Roock, Wendy ;

Claes, Bart ;

Bernasconi, David ;

De Schutter, Jef ;

Biesmans, Bart ;

Fountzilas, George ;

Kalogeras, Konstantine T. ;

Kotoula, Vassiliki ;

Papamichael, Demetris ;

Laurent-Puig, Pierre ;

Penault-Llorca, Frederique ;

Rougier, Philippe ;

Vincenzi, Bruno ;

Santini, Daniele ;

Tonini, Giuseppe ;

Cappuzzo, Federico ;

Frattini, Milo ;

Molinari, Francesca ;

Saletti, Piercarlo ;

De Dosso, Sara ;

Martini, Miriam ;

Bardelli, Alberto ;

Siena, Salvatore ;

Sartore-Bianchi, Andrea ;

Tabernero, Josep ;

Macarulla, Teresa ;

Di Fiore, Frederic ;

Gangloff, Alice Oden ;

Ciardiello, Fortunato ;

Pfeiffer, Per ;

Qvortrup, Camilla ;

Hansen, Tine Plato ;

Van Cutsem, Eric ;

Piessevaux, Hubert ;

Lambrechts, Diether ;

Delorenzi, Mauro ;

Tejpar, Sabine .

LANCET ONCOLOGY, 2010, 11 (08) :753-762

[6]

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials [J].

Dienstmann, Rodrigo ;

Serpico, Danila ;

Rodon, Jordi ;

Saura, Cristina ;

Macarulla, Teresa ;

Elez, Elena ;

Alsina, Maria ;

Capdevila, Jaume ;

Perez-Garcia, Jose ;

Sanchez-Olle, Gessami ;

Aura, Claudia ;

Prudkin, Ludmila ;

Landolfi, Stefania ;

Hernandez-Losa, Javier ;

Vivancos, Ana ;

Tabernero, Josep .

MOLECULAR CANCER THERAPEUTICS, 2012, 11 (09) :2062-2071

[7]

Dietrich S, 2012, NEW ENGL J MED, V366, P2038, DOI 10.1056/NEJMc1202124

[8]

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. [J].

Druker, BJ ;

Talpaz, M ;

Resta, DJ ;

Peng, B ;

Buchdunger, E ;

Ford, JM ;

Lydon, NB ;

Kantarjian, H ;

Capdeville, R ;

Ohno-Jones, S ;

Sawyers, CL .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (14) :1031-1037

[9]

BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes [J].

El-Osta, Hazem ;

Falchook, Gerald ;

Tsimberidou, Apostolia ;

Hong, David ;

Naing, Aung ;

Kim, Kevin ;

Wen, Sijin ;

Janku, Filip ;

Kurzrock, Razelle .

PLOS ONE, 2011, 6 (10)

[10]

Targeting PI3K signalling in cancer: opportunities, challenges and limitations [J].

Engelman, Jeffrey A. .

NATURE REVIEWS CANCER, 2009, 9 (08) :550-562

← 1 2 3 4 →