title: Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.
abstract: KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Conti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Majorini
authors.affiliation: The Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.affiliation: The Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.|Current Address: UCSF Helen Diller Family Comprehensive Cancer Centre, San Francisco, California, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: The Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.|FIRC Institute of Molecular Oncology (IFOM), Milano, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.|FIRC Institute of Molecular Oncology (IFOM), Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, Milan, Italy.
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, University College London, London, UK.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D042361:Mammary Glands, Human / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; Smac mimetics; camptothecin; colorectal cancer