Ink4a/Arf loss promotes tumor recurrence following Ras inhibition

Abstract

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 wellestablished 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.

Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

“…RCASBP(A) Cre, Tet-off and MEK GF have been previously described (36,42), as has RCANBP(A)TRE (43). MEK GF is a constitutively active MEK1 with S218E and S222D substitutions, and lacking residues 32–51 (ΔN3).…”

Cancer Genes and Chromosome Instability

“…For example, MYCinduced lung cancers after oncogene inactivation failed to regress completely because of secondary activating events in K-RAS associated pathways [212] and the loss of TP53 resulted in the absence of tumor regression [213], whereas loss of one TP53 allele dramatically facilitated the progression of WNT1-induced mammary tumors to a oncogene independent state both by impairing the regression of primary tumors and by promoting the recurrence of fully regressed tumors following oncogene inactivation [214]. The acquisition of oncogene independence and tumor recurrence in K-RAS glioma model coincided with loss of CDKN2A [215]. Concurrent mutational inactivation of the PTEN and RB1 tumor suppressors was determined as a mechanism for loss of B-RAF/MEK dependence in melanomas harboring B-RAF mutations [216].…”

Akt Signaling Accelerates Tumor Recurrence Following Ras Inhibition in the Context of Ink4a/Arf Loss

“…We have further shown that in the context of Ink4a/Arf loss, inhibition of KRas is also sufficient to significantly decrease tumor burden. 12 However, tumors became resistant in half of the mice in this context, suggesting that Ink4a/ Arf loss enhances the emergence of recurrent tumors. 12 In this study, we sought to extend our current findings and examine the role of Akt signaling, in combination with activated KRas and loss of Ink4a/Arf, on the growth and recurrence of brain tumors following suppression of KRas expression.…”

“…12 However, tumors became resistant in half of the mice in this context, suggesting that Ink4a/ Arf loss enhances the emergence of recurrent tumors. 12 In this study, we sought to extend our current findings and examine the role of Akt signaling, in combination with activated KRas and loss of Ink4a/Arf, on the growth and recurrence of brain tumors following suppression of KRas expression. Despite the initial dependency of these primary gliomas on continued KRas signaling, tumors progressed to a more aggressive, KRas-independent, high-grade glioma in 70% of the mice.…”