KRAS insertion mutations are oncogenic and exhibit distinct functional properties

Yasmine White, Aditi Bagchi, Jessica Van Ziffle, Anagha Inguva, Gideon Bollag, Chao Zhang, Heidi Carias, David Dickens, Mignon Loh, Kevin Shannon () and Ari J. Firestone ()
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Yasmine White: University of California
Aditi Bagchi: Department of Pediatrics, Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation; Helen DeVos Children’s Hospital/Spectrum Health Medical Group
Jessica Van Ziffle: University of California
Anagha Inguva: University of California
Gideon Bollag: Plexxikon Inc
Chao Zhang: Plexxikon Inc
Heidi Carias: Plexxikon Inc
David Dickens: Department of Pediatrics, Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation; Helen DeVos Children’s Hospital/Spectrum Health Medical Group
Mignon Loh: University of California
Kevin Shannon: University of California
Ari J. Firestone: University of California

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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 of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-RasG60_A66dup and K-RasE62_A66dup proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications.

Date: 2016
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DOI: 10.1038/ncomms10647

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