Literature DB >> 25516890

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

Anthony W Tolcher1, Khurum Khan2, Michael Ong2, Udai Banerji2, Vassiliki Papadimitrakopoulou3, David R Gandara4, Amita Patnaik1, Richard D Baird2, David Olmos2, Christopher R Garrett3, Jeffrey M Skolnik5, Eric H Rubin6, Paul D Smith5, Pearl Huang6, Maria Learoyd5, Keith A Shannon6, Anne Morosky6, Ernestina Tetteh6, Ying-Ming Jou6, Kyriakos P Papadopoulos1, Victor Moreno2, Brianne Kaiser1, Timothy A Yap2, Li Yan6, Johann S de Bono7.   

Abstract

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL
DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily.
RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma.
CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). ©2014 American Association for Cancer Research.

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Year:  2014        PMID： 25516890      PMCID： PMC4335074          DOI： 10.1158/1078-0432.CCR-14-1901

Source DB:  PubMed          Journal:  Clin Cancer Res        ISSN： 1078-0432            Impact factor:   12.531


  29 in total

1.  Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).

Authors:  Sarah V Holt; Armelle Logie; Barry R Davies; Denis Alferez; Sarah Runswick; Sarah Fenton; Christine M Chresta; Yi Gu; Jingchuan Zhang; Yi-Long Wu; Robert W Wilkinson; Sylvie M Guichard; Paul D Smith
Journal:  Cancer Res       Date:  2012-01-23       Impact factor: 12.701

2.  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.

Authors:  Anirudh Prahallad; Chong Sun; Sidong Huang; Federica Di Nicolantonio; Ramon Salazar; Davide Zecchin; Roderick L Beijersbergen; Alberto Bardelli; René Bernards
Journal:  Nature       Date:  2012-01-26       Impact factor: 49.962

3.  Knockdown of PAK4 or PAK1 inhibits the proliferation of mutant KRAS colon cancer cells independently of RAF/MEK/ERK and PI3K/AKT signaling.

Authors:  Hana Tabusa; Teresa Brooks; Andrew J Massey
Journal:  Mol Cancer Res       Date:  2012-12-10       Impact factor: 5.852

Review 4.  Combinatorial drug therapy for cancer in the post-genomic era.

Authors:  Bissan Al-Lazikani; Udai Banerji; Paul Workman
Journal:  Nat Biotechnol       Date:  2012-07-10       Impact factor: 54.908

Review 5.  RAS oncogenes: weaving a tumorigenic web.

Authors:  Yuliya Pylayeva-Gupta; Elda Grabocka; Dafna Bar-Sagi
Journal:  Nat Rev Cancer       Date:  2011-10-13       Impact factor: 60.716

6.  A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens.

Authors:  Jaafar Bennouna; Istvan Lang; Manuel Valladares-Ayerbes; Katalin Boer; Antoine Adenis; Pilar Escudero; Tae-You Kim; Gillian M Pover; Clive D Morris; Jean-Yves Douillard
Journal:  Invest New Drugs       Date:  2010-02-02       Impact factor: 3.850

7.  Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study.

Authors:  Pasi A Jänne; Alice T Shaw; José Rodrigues Pereira; Gaëlle Jeannin; Johan Vansteenkiste; Carlos Barrios; Fabio Andre Franke; Lynda Grinsted; Victoria Zazulina; Paul Smith; Ian Smith; Lucio Crinò
Journal:  Lancet Oncol       Date:  2012-11-28       Impact factor: 41.316

8.  A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.

Authors:  Udai Banerji; Leni van Doorn; Dionysis Papadatos-Pastos; Rebecca Kristeleit; Phillip Debnam; Matthew Tall; Adam Stewart; Florence Raynaud; Michelle Dawn Garrett; Martin Toal; Leon Hooftman; Johann Sebastian De Bono; Jaap Verweij; Ferry Alm Eskens
Journal:  Clin Cancer Res       Date:  2012-05-01       Impact factor: 12.531

9.  Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies.

Authors:  Michael Steckel; Miriam Molina-Arcas; Britta Weigelt; Michaela Marani; Patricia H Warne; Hanna Kuznetsov; Gavin Kelly; Becky Saunders; Michael Howell; Julian Downward; David C Hancock
Journal:  Cell Res       Date:  2012-05-22       Impact factor: 25.617

10.  K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.

Authors:  Irmgard Hofmann; Andreas Weiss; Gaelle Elain; Maria Schwaederle; Dario Sterker; Vincent Romanet; Tobias Schmelzle; Albert Lai; Saskia M Brachmann; Mohamed Bentires-Alj; Thomas M Roberts; William R Sellers; Francesco Hofmann; Sauveur-Michel Maira
Journal:  PLoS One       Date:  2012-08-31       Impact factor: 3.240
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  57 in total

1.  Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models.

Authors:  Chaoxin Hu; Tikva Dadon; Venugopal Chenna; Shinichi Yabuuchi; Rajat Bannerji; Robert Booher; Peter Strack; Nilofer Azad; Barry D Nelkin; Anirban Maitra
Journal:  Mol Cancer Ther       Date:  2015-04-30       Impact factor: 6.261

2.  Combined MEK and BCL-2/XL Inhibition Is Effective in High-Grade Serous Ovarian Cancer Patient-Derived Xenograft Models and BIM Levels Are Predictive of Responsiveness.

Authors:  Claudia Iavarone; Ioannis K Zervantonakis; Laura M Selfors; Sangeetha Palakurthi; Joyce F Liu; Ronny Drapkin; Ursula A Matulonis; Dorothy Hallberg; Victor E Velculescu; Joel D Leverson; Deepak Sampath; Gordon B Mills; Joan S Brugge
Journal:  Mol Cancer Ther       Date:  2019-01-24       Impact factor: 6.261

3.  Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.

Authors:  Khanh Do; Giovanna Speranza; Rachel Bishop; Sonny Khin; Larry Rubinstein; Robert J Kinders; Manuel Datiles; Michelle Eugeni; Michael H Lam; L Austin Doyle; James H Doroshow; Shivaani Kummar
Journal:  Invest New Drugs       Date:  2015-02-01       Impact factor: 3.850

4.  Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models.

Authors:  Andrea Wang-Gillam; Kian-Huat Lim; Hongmei Jiang; Mai Xu; Lin Li; Patrick Grierson; Paarth Dodhiawala; Maureen Highkin; Daoxiang Zhang; Qiong Li
Journal:  Mol Cancer Ther       Date:  2018-07-31       Impact factor: 6.261

5.  The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

Authors:  Vassiliki Papadimitrakopoulou; J Jack Lee; Ignacio I Wistuba; Anne S Tsao; Frank V Fossella; Neda Kalhor; Sanjay Gupta; Lauren Averett Byers; Julie G Izzo; Scott N Gettinger; Sarah B Goldberg; Ximing Tang; Vincent A Miller; Ferdinandos Skoulidis; Don L Gibbons; Li Shen; Caimiao Wei; Lixia Diao; S Andrew Peng; Jing Wang; Alda L Tam; Kevin R Coombes; Ja Seok Koo; David J Mauro; Eric H Rubin; John V Heymach; Waun Ki Hong; Roy S Herbst
Journal:  J Clin Oncol       Date:  2016-10-20       Impact factor: 44.544

6.  Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers.

Authors:  Lorna Rodriguez-Rodriguez; Kim M Hirshfield; Veronica Rojas; Robert S DiPaola; Darlene Gibbon; Mira Hellmann; Sara Isani; Aliza Leiser; Gregory M Riedlinger; Allison Wagreich; Siraj M Ali; Julia A Elvin; Vincent A Miller; Shridar Ganesan
Journal:  Gynecol Oncol       Date:  2016-04       Impact factor: 5.482

7.  Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression.

Authors:  Tikvah K Hayes; Nicole F Neel; Chaoxin Hu; Prson Gautam; Melissa Chenard; Brian Long; Meraj Aziz; Michelle Kassner; Kirsten L Bryant; Mariaelena Pierobon; Raoud Marayati; Swapnil Kher; Samuel D George; Mai Xu; Andrea Wang-Gillam; Ahmed A Samatar; Anirban Maitra; Krister Wennerberg; Emanuel F Petricoin; Hongwei H Yin; Barry Nelkin; Adrienne D Cox; Jen Jen Yeh; Channing J Der
Journal:  Cancer Cell       Date:  2015-12-24       Impact factor: 31.743

Review 8.  RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.

Authors:  Bingliang Fang
Journal:  Acta Biochim Biophys Sin (Shanghai)       Date:  2015-09-07       Impact factor: 3.848

9.  Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

Authors:  Anthony W Tolcher; Razelle Kurzrock; Vincente Valero; Rene Gonzalez; Rebecca S Heist; Antoinette R Tan; Julie Means-Powell; Theresa L Werner; Carlos Becerra; Chenxi Wang; Cathrine Leonowens; Shanker Kalyana-Sundaram; Joseph F Kleha; Jennifer Gauvin; Anthony M D'Amelio; Catherine Ellis; Nageatte Ibrahim; Li Yan
Journal:  Cancer Chemother Pharmacol       Date:  2020-02-15       Impact factor: 3.333

10.  Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma.

Authors:  Xiaoyan Ren; Yifei Liu; Yumei Tao; Guoxiang Zhu; Meilan Pei; Jianguo Zhang; Jian Liu
Journal:  Oncol Lett       Date:  2016-03-17       Impact factor: 2.967
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