Targeting the RB-pathway in Cancer Therapy

Abstract

The RB-pathway, consisting of inhibitors and activators of cyclin-dependent kinases, the retinoblastoma tumor suppressor (RB), and the E2F-family of transcription factors, plays critical roles in the regulation of cell cycle progression and cell death. Components of this pathway, particularly p16Ink4a, cyclin D1, and RB, are frequently altered in sporadic human cancers to promote deregulated cellular proliferation. The consistent disruption of the RB-pathway in human cancers raises the possibility of exploiting tumor-specific RB-pathway defects to improve the efficacy of current therapies and to develop new therapeutic strategies. This article discusses how the RB-pathway status impacts the cellular responses to cytotoxic, cytostatic, and hormone therapies, and how the components of the RB-pathway may be directly targeted to treat cancer.

Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors

“…11,12,14 RB is the proto-typical tumor suppressor that functions downstream of CDK4/6 to modulate cell cycle progression. [15][16][17] Tumors that are RB-deficient express exceedingly high levels of p16ink4a. 17 Therefore, to determine the basis for the differential response to PD-033299 in the explanted tissues, both the primary tumors and explants were stained for p16ink4a and RB.…”

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…The cell cycle regulating CDKs are part of the Rb pathway as they function-in complexes with cyclins-to stepwise phosphorylate Rb, resulting in the activation of E2F-mediated transcription and cell cycle progression (Giacinti and Giordano, 2006). As with all second-generation CDK inhibitors, the CDK inhibitor roscovitine shows preferable activity against one CDK (the Rb pathway component CDK2), but it also inhibits other CDKs (especially CDK7/9) (Knudsen and Wang, 2010). We found that roscovitine induced changes in the expression of proteins involved in the Rb pathway.…”

The meaning of p16ink4aexpression in tumors

“…49 The reason for this is not fully known, although multiple preclinical models have shown that disruption of RB function renders cells and tumors sensitive to cytotoxic therapies, 50,51 and perhaps both HPV and somatic loss of RB are occurring in head and neck cancers yielding increased sensitivity to radiotherapy. Importantly, these findings have been recapitulated in multiple distinct cohorts and suggest that p16 ink4a status can be deployed prospectively to define head and neck cancers that will exhibit an improved response to radiation.…”