title: Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation.
abstract: KRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeutics must be explored. Our objective was to study efficacy of two drugs with different mechanisms of action, everolimus (mTOR inhibitor) and lapatinib (tyrosine kinase inhibitor), in a mouse xenograft model. We chose a model obtained after engraftment of a tumor originating from a human tumor collection. The patient was affected by a metastasis colorectal carcinoma resistant to cetuximab with KRAS mutation. From a previous study in mice, we know that everolimus is a P-glycoprotein (P-gp) substrate and that a lapatinib pretreatment increases significantly (2.6-fold) everolimus AUC by inhibiting its intestinal P-gp efflux. We hence tested the effect of these drugs alone or combined. Mice bearing the xenografts were divided in four groups: control, lapatinib, everolimus, and L/E group (L/E: 2 days of lapatinib 200 mg/kg and then 3 days of everolimus 1 mg/kg). Tumor volumes and treatment toxicities were evaluated. Sixteen days after treatment initiation, the group L/E was the first one in which tumor volume average was significantly lower than the one of control group (193 ± 90 vs. 395 ± 171 mm(3) ; P = 0.0025). After 4 weeks of treatment, inhibition of tumor growth in lapatinib, everolimus, and L/E groups reached, respectively, 49, 53, and 57%. Each drug showed significant antitumor activity. Only moderate hematologic toxicity signs were observed. These results lead to new perspectives for new oral drugs in metastatic KRAS-mutated colorectal cancer resistant to standard chemotherapy.
authors.affiliation: Laboratory of Pharmacology, Hôpital Paul Brousse, 14 Avenue Paul Vaillant-Couturier, 94800 Villejuif, France. celine.chu@yahoo.fr
authors.forename: Céline
authors.initials: C
authors.lastname: Chu
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Noël-Hudson
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Diane
authors.initials: D
authors.lastname: Goéré
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marion
authors.forename: Mélanie
authors.initials: M
authors.lastname: Polrot
authors.forename: Ludovic
authors.initials: L
authors.lastname: Bigot
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonin
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Laurence
authors.initials: L
authors.lastname: Bonhomme-Faivre
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D011799:Quinazolines; D000077341:Lapatinib; D000068338:Everolimus; D018631:ras Proteins; D020123:Sirolimus