title: ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition.
abstract: K-RAS mutated (K-RASmut) non-small cell lung cancer (NSCLC) cells are resistant to EGFR targeting strategies. We investigated the impact of K-RAS activity irrespective of mutational status in the EGFR-independent increase in clonogenic cell survival. An analysis of the K-RAS activity status revealed a constitutively high K-RAS activity in K-RASmut NSCLC cells and also in head and neck squamous cell carcinoma (HNSCC) cells overexpressing wild-type K-RAS (K-RASwt). Similar to K-RAS-mutated cells, increased K-RAS activity in HNSCC cells overexpressing K-RASwt was associated with the stimulated production of the EGFR ligand amphiregulin and resistance to EGFR tyrosine kinase (EGFR-TK) inhibitors such as erlotinib. Expression of mutated K-RAS stimulated Akt phosphorylation and increased plating efficiency. Conversely, knockdown of K-RAS in K-RASmut NSCLC cells and in HNSCC cells presenting overexpression of K-RASwt resulted in sensitization to the anti-clonogenic activity of erlotinib. K-RAS activity results in EGFR-dependent and EGFR-independent Akt activity. The short-term treatment (2 h) of cells with EGFR-TK or PI3K inhibitors (erlotinib and PI-103) resulted in the repression of Akt activation, whereas long-term treatment (24 h) with inhibitors led to the reactivation of Akt and improved clonogenicity. The Akt re-activation was MAPK-ERK2-dependent and associated with a lack of complete response to anti-clonogenic activity of PI-103. A complete response was observed when PI-103 was combined with MEK inhibitor PD98059. Together, clonogenicity inhibition in tumor cells presenting constitutive K-RAS activity independent of K-RAS mutational status can be achieved by targeting of EGFR downstream pathways, i.e., PI3K alone or the combination of PI3K and MAPK inhibitors.
authors.affiliation: Division of Radiobiology and Molecular Environmental Research; Department of Radiation Oncology; Eberhard Karls University Tuebingen; Tuebingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
authors.affiliation: Division of Radiobiology and Molecular Environmental Research; Department of Radiation Oncology; Eberhard Karls University Tuebingen; Tuebingen, Germany.
authors.forename: Minjmaa
authors.initials: M
authors.lastname: Minjgee
authors.affiliation: Division of Radiobiology and Molecular Environmental Research; Department of Radiation Oncology; Eberhard Karls University Tuebingen; Tuebingen, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Saki
authors.affiliation: Division of Radiobiology and Molecular Environmental Research; Department of Radiation Oncology; Eberhard Karls University Tuebingen; Tuebingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Holler
authors.affiliation: Division of Dermatologic Oncology; Department of Dermatology; University of Tuebingen; Tuebingen, Germany.
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
authors.affiliation: Department of Radiotherapy; University of Dresden; Dresden, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eicheler
authors.affiliation: Division of Radiobiology and Molecular Environmental Research; Department of Radiation Oncology; Eberhard Karls University Tuebingen; Tuebingen, Germany.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Rodemann
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005419:Flavonoids / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D006258:Head and Neck Neoplasms; D006801:Humans; D008175:Lung Neoplasms; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D005663:Furans; C117307:KRAS protein, human; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: EGFR; HNSCC; K-RAS; MAPK/ERK; NSCLC; PI-103; PI3K/Akt; erlotinib