CDK4/6 inhibitors in lung cancer: current practice and future directions

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, and ∼85% of lung cancers are classified as nonsmall cell lung cancer (NSCLC). These malignancies can proliferate indefinitely, in part due to dysregulation of the cell cycle and the resulting abnormal cell growth. The specific activation of cyclin-dependent kinases 4 and 6 (CDK4/6) is closely linked to tumour proliferation. Approximately 80% of human tumours exhibit abnormalities in the cyclin D-CDK4/6-INK4-RB pathway. Specifically, CDK4/6 inhibitors either as monotherapy or combination therapy have been investigated in pre-clinical and clinical studies for the treatment of NSCLC, and promising results have been achieved. This review article focuses on research regarding the use of CDK4/6 inhibitors in NSCLC, including the characteristics and mechanisms of action of approved drugs and progress of pre-clinical and clinical research.

FIGURE 1

Classical model of G1–S transition regulated by cyclins and cyclin-dependent kinases (CDK). The cyclin D–CDK4/6 complex can be activated through Janus kinase–signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT), and Ras–Raf–extracellular signal-regulated protein kinases (ERK) signalling pathways, and is regulated by P16INK4A inhibition. Furthermore, CDK inactivation can be mediated through P21CIP1 via the P53 signalling pathway. Generally, inhibition of CDK4/6 and CDK2 leads to lower phosphorylation of retinoblastoma (RB), which in turn inhibits the expression of early region 2 (E2F) target genes. CDK2 is activated in the G1 phase with a rise in late-stage E-type cyclin levels, leading to overphosphorylation and deactivation of RB. Overphosphorylated RB is released from E2F, resulting in increased transcription of E2F target genes, which is necessary for the cell to enter the S phase. mTOR: mammalian target of rapamycin; TGF: transforming growth factor.

FIGURE 2

Effect of cyclin-dependent kinase (CDK)4/6 inhibition on tumour immune microenvironment. CDK4/6 inhibitors may not only have tumour-specific functions, but also affect the tumour microenvironment. In tumour cells, CDK4/6 inhibitors increase programmed cell death ligand 1 (PD-L1) expression via the E3 ligase connector protein SPOt-type POZ protein (SPOP) and enhance antigen presentation by decreasing early region 2 (E2F) target DNA methyltransferase (DNMT)1 activity. Treatment with CDK4/6 inhibitors also increases cytokine secretion in tumour and CD8⁺ T-cells, while inhibiting the proliferation of immunosuppressive regulatory T-cells (Tregs). ERV: endogenous retrovirus; dsRNA: double-stranded RNA; MHC: major histocompatibility complex; IFN: interferon; NFAT: nuclear factor of activated T-cells.

FIGURE 3

Conceptual framework for the main combination strategies for cyclin-dependent kinase (CDK)4/6 inhibitors. a) CDK4/6 can be used in combination with chemotherapy and should be used after chemotherapy, rather than before or at the same time as chemotherapy, to avoid interfering with chemotherapy by preventing G1/S transition in advance and to prevent recovery after damage has been determined. b) CDK4/6 inhibitors can be combined with radiotherapy drugs. c) CDK4/6 inhibitors enhance the efficacy of immunotherapy by allowing the expression of immune checkpoint proteins (retinoblastoma (RB)1-dependent and -independent) and by the antiproliferative effect of immune-suppressive cells such as regulatory T-cells (Tregs) (RB1-dependent). d) In addition, CDK4/6 inhibitors can be combined with targeted agents, such as epidermal growth factor receptor (EGFR) inhibitors, MEK inhibitors, mammalian target of rapamycin (mTOR) inhibitors and phosphatidylinositol 3-kinase (PI3K)CA.