Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM

Abstract

Glioblastoma multiforme (GBM) is a fatal primary brain tumor harboring myriad genetic and epigenetic alterations. The recent multidimensional analysis of the GBM genome has provided a more complete view of the landscape of such alterations and their linked pathways. This effort has demonstrated that certain pathways are universally altered, but that the specific genetic events altered within each pathway can vary for each particular patient's tumor. With this atlas of genetic and epigenetic events, it now becomes feasible to assess how the patterns of mutations in a pathway influence response to drugs that are targeting such pathways. This issue is particularly important for GBM because, in contrast to other tumor types, molecularly targeted therapies have failed to alter overall survival substantially. Here, we combined functional genetic screens and comprehensive genomic analyses to identify CDK6 as a GBM oncogene that is required for proliferation and viability in a subset of GBM cell lines and tumors. Using an available small molecule targeting cyclin-dependent kinases (CDKs) 4 and 6, we sought to determine if the specific pattern of retinoblastoma pathway inactivation dictated the response to CDK4/6 inhibitor therapy. We showed that codeletion of CDKN2A and CDKN2C serves as a strong predictor of sensitivity to a selective inhibitor of CDK4/6. Thus, genome-informed drug sensitivity studies identify a subset of GBMs likely to respond to CDK4/6 inhibition. More generally, these observations demonstrate that the integration of genomic, functional and pharmacologic data can be exploited to inform the development of targeted therapy directed against specific cancer pathways.cyclin-dependent kinase inhibitor | INK4C | PD0332991 | targeted therapy C omprehensive genomic characterization of glioblastoma multiforme (GBM) has revealed major cancer-relevant pathways that are near-universally targeted for genetic or epigenetic alterations that regulate the activity of such pathways (1). Against the backdrop of an increasing appreciation for the highly heterogeneous and complex nature of the cancer genome, targeting these common pathways as a therapeutic strategy is appealing in comparison with sorting through the myriad of driver and passenger alterations for therapeutic targets that may only be relevant in a small subset of the tumors. Consistent with rapid and unrestrained proliferation that is characteristic of tumor cells, the retinoblastoma (RB) pathway is found to be nearly universally inactivated in human cancers, including glioblastoma (2). At the nexus of this pathway is the RB protein itself, the central regulator of cell cycle progression through its inhibitory effect on E2F transcription factors that in turn regulate key genes involved in proliferation. RB is tightly regulated by the opposing activating cyclindependent kinases 4 and 6 (CDK4/6) and their cyclin-D binding partners, as well as the inactivating CDK inhibitors (CKIs) such as p16 INK4A (CDKN2A) and p18 INK4C(CDKN2C) (3). Genetic alterations target...

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“…This was confirmed also in ex vivo studies on primary human tumor cultures [Dean et al 2012b]. CDK4 mutations [Young et al 2014], CDKN2A and CDKN2C (encoding p18 INK4C ) deletions [Wiedemeyer et al 2010] and low E2F expression [Logan et al 2013] have been shown to predict palbociclib response in other tumor types, whereas high expression of cyclin E1 [Konecny et al 2011] was associated with resistance.…”

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

“…The CDK6 gene is frequently amplified or overexpressed in a variety of human cancers (Grossel and Hinds, 2006a), such as glioblastoma (Wiedemeyer et al, 2010), myxofibrosarcoma (Tsai et al, 2012), and lymphoid malignancies (Nagel et al, 2008). By accelerating progression through G1/S phase checkpoint of the cell cycle, overexpression of CDK6 increased cell proliferation and reduced DNA repair capacity.…”

SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans

“…Since p16INK4a inhibits CDK4/6, which inactivates RB by phosphorylation, and since p19ARF (or P14ARF) targets MDM2, which suppresses p53 (5), we thus examined responses of modulating CDK4/6 and p53 in these cells. As shown in Figure 4E, inhibition of phosphorylation of RB, the direct downstream target of CDK4/6 by CDK4/6 inhibitor PD0332991 (20), markedly reduced PDGF-A-stimulated cell growth of Ink4a/Arf-deficient mAsts and LN444 cells in soft agar, which suggests that the tumorigenic effect of PDGFRα signaling is dependent on CDK4/6 inactivation of RB proteins (p-RB). Since we did not observe any tumor-suppressing effect of p19ARF on Ink4a/Arf -/-PDGFRα-expressing mAsts ( Figure 4B), we asked whether the downstream p53 protein was functional in these cells.…”