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G48A, a New KRAS Mutation Found in Lung Adenocarcinoma

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Presentation on theme: "G48A, a New KRAS Mutation Found in Lung Adenocarcinoma"— Presentation transcript:

1 G48A, a New KRAS Mutation Found in Lung Adenocarcinoma
Mirko Marabese, PhD, Elisa Caiola, PhD, Marina C. Garassino, MD, Giulio Rastelli, PhD, Giulio Settanni, PhD, Sonia Brugnara, MD, Massimo Broggini, PhD, Monica Ganzinelli, PhD  Journal of Thoracic Oncology  Volume 11, Issue 7, Pages (July 2016) DOI: /j.jtho Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

2 Figure 1 (A) Sanger sequencing chromatogram showing the G48A mutation in Kirsten rat sarcoma viral oncogene homolog gene (KRAS). (B) Representative Western blot analysis demonstrating comparable expression of exogenous KRAS variants in the isolated clones. Tubulin was used as a loading control. (C) In vitro growth of NCI-H1299 clones expressing wild-type and KRAS mutations. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

3 Figure 2 (A) Response of NCI-H1299 clones to cisplatin, detected by MTS assay. The average of three independent experiments and SD are shown. (B) Response of NCI-H1299 clones to pemetrexed, detected by MTS assay. The average of three independent experiments and SD are shown. KRAS, Kirsten rat sarcoma viral oncogene homolog; SD, standard deviation. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

4 Figure 3 (A) In vitro growth of NCI-H2228 clones expressing wild-type and KRAS(G48A) mutation. (B) Response of NCI-H2228 clones to cisplatin, detected by RealTime-Glo MT Cell Viability assay. The average of three independent experiments and SD are shown. KRAS, Kirsten rat sarcoma viral oncogene homolog; SD, standard deviation. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

5 Figure 4 (A) Crystal structure of Kirsten rat sarcoma viral oncogene homolog (KRAS) bound to guanosine diphosphate (Protein Data Bank code 4OBE), showing the location of residue G48 in relation to guanosine diphosphate and switches 1 and 2. (B) Close-up of the structure of the type I’ β-turn connecting β2 and β3, in which G48 is the i+2 residue. (C) Hydrogen bonds between residue R164 of helix α5 and the backbone carbonyls of residues I46 and E49 of the β-turn. (D) Levels of GTP-KRAS in NCI-H1299 clones measured by pull-down with the recombinant RAS-binding domain of RAF and detected by anti-KRAS antibody. Total lysates were also immunoblotted with anti-KRAS, anti–extracellular signal–regulated kinase (ERK), and anti-p-ERK. Anti-tubulin antibody was used as a loading control. (E) Interaction of KRAS(wt), KRAS(G12C), and KRAS(G48A) to B-Raf proto-oncogene, serine/threonine kinase measured in NCI-H1299 cells with a fluorescence-based assay. (F) levels of ERK (left) and p-ERK (right) detected by immunohistochemical analysis of the patient’s biopsy specimen. (G) Levels of phosphorylated proteins compared with the control clone arbitrarily set to 100. Journal of Thoracic Oncology  , DOI: ( /j.jtho ) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

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