Retinoblastoma-p16INK4a signaling pathway (Rb/p16 pathway)

The Rb/p16-defective tumor cell cycle pathway is a central regulatory axis that governs the G1-to-S phase transition, a critical checkpoint often subverted in human malignancies (Sherr & McCormick, 2002 [1]). This pathway is composed of the tumor suppressor p16INK4a, which inhibits the Cyclin D-dependent kinases CDK4 and CDK6, and the Retinoblastoma (Rb) protein, which acts as a transcriptional repressor of S-phase genes (Weinberg, 1995 [2]). In a normal cellular context, p16INK4a prevents CDK4/6 from phosphorylating Rb, thereby maintaining Rb in its active state to halt cell cycle progression (Dick & Rubin, 2013 [3]). Dysregulation of this pathway—through CDKN2A (p16) deletion, CCND1 (Cyclin D1) amplification, or RB1 (Rb) loss—results in constitutive E2F-mediated transcription and unchecked cell proliferation (Hanahan & Weinberg, 2011 [4]). Therapeutic strategies targeting this axis primarily utilize selective CDK4/6 inhibitors like palbociclib and ribociclib to restore G1 arrest; however, these agents require a functional Rb protein for efficacy, making RB1 status a primary biomarker for treatment response (O'Leary et al., 2016 [5]). Consequently, tumors with Rb-deficiency are inherently resistant to CDK4/6 inhibition, necessitating alternative therapeutic approaches for these subsets (Knudsen & Witkiewicz, 2017 [6]).

Other names

p16-Cyclin D-CDK4/6-Rb axisRB pathwayG1/S checkpoint pathwayp16INK4a-RB1 pathway

Selective inhibition of Cyclin-dependent kinases 4 and 6 (CDK4/6) to prevent the phosphorylation of the Retinoblastoma (Rb) protein, thereby maintaining Rb in its active, E2F-binding state and inducing G1 phase cell cycle arrest.