title: The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer.
abstract: OBJECTIVE
  This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.
  
  
  METHODS
  We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.
  
  
  RESULTS
  Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.
  
  
  CONCLUSIONS
  These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth.
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center, San Antonio, Texas 78229, USA.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Drew W
authors.initials: DW
authors.lastname: Rasco
authors.forename: Lon S
authors.initials: LS
authors.lastname: Smith
authors.forename: Shelly
authors.initials: S
authors.lastname: Gunn
authors.forename: Leslie
authors.initials: L
authors.lastname: Smetzer
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Mays
authors.forename: Brianne
authors.initials: B
authors.lastname: Kaiser
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wick
authors.forename: Cathy
authors.initials: C
authors.lastname: Alvarez
authors.forename: Aracely
authors.initials: A
authors.lastname: Cavazos
authors.forename: Gina L
authors.initials: GL
authors.lastname: Mangold
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C482119:BRAF protein, human