title: Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing.
abstract: Understanding genetic aberrations in cancer leads to discovery of new targets for cancer therapies. The genomic landscape of hepatocellular carcinoma (HCC) has not been fully described. Therefore, patients with refractory advanced/metastatic HCC referred for experimental therapies, who had adequate tumor tissue available, had targeted next generation sequencing (NGS) of their tumor samples using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA) and their treatment outcomes were analyzed. In total, NGS was obtained for 14 patients (median number of prior therapies, 1) with advanced/metastatic HCC. Of these 14 patients, 10 (71%) were men, 4 (29%) women, 6 (43%) had hepatitis B or C-related HCC. NGS revealed at least 1 molecular abnormality in 12 patients (range 0-8, median 2). Detected molecular aberrations led to putative activation of the PI3K/AKT/mTOR pathway (n=3 [mTOR, PIK3CA, NF1]), Wnt pathway (n=6 [CTNNA1, CTNNB1]), MAPK pathway (n=2 [MAP2K1, NRAS]), and aberrant DNA repair mechanisms, cell cycle control and apoptosis (n=18 [ATM, ATR, BAP1, CCND1, CDKN2A, CDK4, FGF3, FGF4, FGF19, MCL1, MDM2, RB1, TP53]). Of the 3 patients with molecular aberrations putatively activating the PI3K/AKT/mTOR pathway, 2 received therapies including a mTOR inhibitor and all demonstrated therapeutic benefit ranging from a partial response to minor shrinkage per RECIST (-30%, -15%; respectively). In conclusion, genomic alterations are common in advanced HCC. Refractory patients with alterations putatively activating the PI3K/AKT/mTOR pathway demonstrated early signals of clinical activity when treated with therapies targeting mTOR.
authors.affiliation: Departments of Investigational Cancer Therapeutics. Phase I Clinical Trials Program.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Ahmed O
authors.initials: AO
authors.lastname: Kaseb
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.affiliation: Moores Cancer Center, The University of California San Diego, La Jolla, CA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human