title: Antitumor activity in RAS-driven tumors by blocking AKT and MEK.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio Texas.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Khurum
authors.initials: K
authors.lastname: Khan
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Ong
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.affiliation: UC Davis Cancer Center, Sacramento, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Baird
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Pearl
authors.initials: P
authors.lastname: Huang
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Learoyd
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Shannon
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Anne
authors.initials: A
authors.lastname: Morosky
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Tetteh
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Jou
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio Texas.
authors.forename: Brianne
authors.initials: B
authors.lastname: Kaiser
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom. johann.de-Bono@icr.ac.uk.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D045744:Cell Line, Tumor; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D006575:Heterocyclic Compounds, 3-Ring; C117307:KRAS protein, human; C548887:MK 2206; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins