KRAS insertion mutations are oncogenic and exhibit distinct functional properties

• DOI: 10.1038/ncomms10647
• Publication Date: 2016-02-08T10:05:48Z
• Authors: Yasmine White; Aditi Bagchi; Jessica Van Ziffle; Anagha Inguva; Gideon Bollag; Chao Zhang; Heidi Carias; David Dickens; Mignon Loh; Kevin Shannon; Ari J. Firestone
• Keywords: 0301 basic medicine; Science; 610; Juvenile; Article; Proto-Oncogene Proteins p21(ras); Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Rare Diseases; Insertional; Genetics; Animals; Humans; Child; Preschool; Tumor Stem Cell Assay; Cancer; Leukemia; Q; GTPase-Activating Proteins; Myelomonocytic; Biological Sciences; Mutagenesis, Insertional; Orphan Drug; Leukemia, Myelomonocytic, Juvenile; Mutagenesis; Tandem Repeat Sequences; Child, Preschool; Mutation; Hepatocytes; Biochemistry and Cell Biology; Proto-Oncogene Proteins c-akt

Abstract Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain K-Ras encoding tandem repeat acids G60_A66dup in child with an atypical myeloproliferative neoplasm. containing this or similar five E62_A66dup mutation identified lung colon cancers transform growth primary myeloid progenitors Ba/F3 cells. Recombinant display reduced GTP hydrolysis rates, accumulate GTP-bound conformation are resistant GAP-mediated hydrolysis. Remarkably, insertions impaired for PI3 kinase binding Akt activation, hypersensitive MEK inhibition. These studies illuminate new class oncogenic reveal unexpected plasticity has diagnostic therapeutic implications.