Ink4a/Arf loss promotes tumor recurrence following Ras inhibition.
Aberrant activation of rat sarcoma (Ras) signaling contributes to the development of a variety of human cancers, including gliomas. To determine the dependence of high-grade gliomas on continued Ras signaling, we developed a doxycycline-regulated Kirsten Ras (KRas) glioma mouse model. We previously demonstrated that KRas is required for the maintenance of glioblastoma multiforme tumors arising in the context of activated Akt signaling in vivo; inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. We utilized a well-established glioma mouse model to determine the reliance of gliomas on continued KRas signaling in the context of Ink4a/Arf deficiency, a common occurrence in human gliomas. Despite the dependency of primary gliomas on continued KRas signaling, a significant percentage of tumors progressed to a KRas-independent state in the absence of Ink4a/Arf expression, demonstrating that these tumor suppressors play a critical role in the suppression of glioma recurrence. While even advanced stages of gliomas may remain dependent upon KRas signaling for maintenance and growth, our findings demonstrate that loss of Ink4a/Arf facilitates the acquisition of oncogene independence and tumor recurrence. Furthermore, reactivation of the Ras mitogen-activated protein kinase pathway in the absence of virally delivered KRas expression is a common mechanism of recurrence in this context.
Nevada Cancer Institute, Las Vegas, Nevada 89135, USA.
Matthew W
MW
Vanbrocklin
James P
JP
Robinson
Kristin J
KJ
Lastwika
Andrea J
AJ
McKinney
H Michael
HM
Gach
Sheri L
SL
Holmen
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009858:Oncogenic Viruses / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020928:Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)