Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor-based regimens

JCI Insight. 2021 Jan 11;6(1):e142547. doi: 10.1172/jci.insight.142547.


BACKGROUNDAlthough CDK4/6 inhibitors are an established treatment for hormone receptor-positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODSWe investigated factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTSOverall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182-465 genes) and therapy outcome of (non-breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0-24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs. <50%] matching score, PFS, 6.2 vs. 2.0 months, P < 0.001 [n = 40] [multivariate]) and higher rate of stable disease ≥6 months or an objective response (57% vs. 21%, P = 0.048).CONCLUSIONIn summary, in cell-cycle-altered cancers, matched CDK4/6 inhibitors, as part of an individualized regimen targeting a majority of genomic alterations, was independently associated with longer PFS.TRIAL NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, National Cancer Institute (P30 CA023100, R01 CA226803), and the FDA (R01 FD006334).

Keywords: Cell cycle; Molecular biology; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cyclin D / genetics
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • G1 Phase Cell Cycle Checkpoints / genetics*
  • Genes, p16
  • Humans
  • MAP Kinase Signaling System / genetics
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Progression-Free Survival
  • Protein Kinase Inhibitors / therapeutic use
  • Young Adult


  • CDKN2A protein, human
  • CDKN2B protein, human
  • Cyclin D
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Protein Kinase Inhibitors
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6

Associated data