Targeting CDK4/6 to oppose hypoxia-mediated therapeutic resistance

This article refers to:

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

Mounting evidence demonstrates that there is considerable integration between cell cycle progression and the cellular response to hypoxia. As a tumor expands, it quickly outgrows its existing vasculature, exposing a significant portion of the tumor to low oxygen. Hypoxia serves as an environmental cue for cells to stop growing, and causes cell cycle arrest in G1-phase via the transcriptional upregulation of cyclin-dependent kinase (CDK) inhibitors, as well as blocking DNA replication.¹ Cancer cells are able to overcome the normal checks and balances that control and limit cell division in hypoxia by executing a substantial shift in gene expression. These transcriptional changes can largely be attributed to an oxygen sensitive transcription factor known as hypoxia inducible factor-1 (HIF-1). Stabilization of HIF-1 provides an important mechanism by which cancer cells acquire resistance to chemotherapy.²

The ability of HIF-1 to influence cell cycle progression (both positively and negatively) has been well studied. However, mounting evidence indicates that cell cycle regulators can also directly influence the activation state of HIF-1. CDK1 has been shown to directly phosphorylate HIF-1α and block its proteasomal degradation, which acts to enhance cell cycle progression and promote tumorigenesis.³ A subsequent report demonstrated that CDK1 and CDK2 interact with HIF-1 to regulate its degradation by the lysosome.⁴ As a result, there is growing interest in the use of CDK inhibitors to oppose hypoxia-mediated therapeutic resistance.

Previous work from the El-Deiry laboratory demonstrated that combinatorial inhibition of CDK1 and GSK-3β increases the sensitivity of colorectal cancer cells to TRAIL-induced apoptosis.⁵ This study by Zhang et al. expands on those findings and provides compelling data to support the translation of CDK4/6 inhibitors as a strategy to selectively target the hypoxic cancer cell population.⁶ Palbociclib is a selective CDK4/6 inhibitor that has shown clinical benefit in various types of cancer. The authors demonstrate that hypoxic cancer cells are more sensitive to palbociclib compared with normoxic cells. Although hypoxia induces resistance to 5-FU in colorectal cancer cell lines, it does not have this effect on palbociclib (CDK 4/6 inhibitor) or irinotecan (topoisomerase 1 inhibitor). Indicative of the importance of HIF-1 activation for hypoxia-mediated resistance in colon cancer, both irinotecan and palbociclib reduce HIF-1α protein levels, whereas 5-FU does not. Irinotecan reduces HIF-1α by inhibiting its translation.⁷ This study demonstrates that palbociclib destabilizes HIF-1α, suggesting a new mechanism for the anti-tumor effects of CDK4/6 inhibitors, independent of the cell cycle.

Based on this knowledge, Zhang et al. tested the efficacy of combining palbociclib with first line therapies for colon cancer. The authors found that palbociclib acts synergistically with a variety of chemotherapies in hypoxia. Notably, the combination of irinotecan and palbociclib displayed significant synergy in a genetically varied set of colon cancer cells lines harboring mutations in KRAS, BRAF, and p53. Mechanistically, the authors show that the cytotoxic effect of this combination is multifaceted, involving the loss of GSK-3β expression, decreased Rb phosphorylation, and reduced HIF-1 accumulation. Combined inhibition of CDK4/6 and topoisomerase 1 reduced HIF-1α levels to a greater extent than either agent alone. Interestingly, single agent treatment with irinotecan increased Rb phosphorylation in hypoxia, and the addition of palbociclib abolished this effect. This finding suggests that palbociclib could return Rb to a hypophosphorylated state following treatment with irinotecan in hypoxia, which favors cell cycle arrest and senescence. In the future, it will be important to validate CDK4/6 inhibitors as hypoxia-targeting agents in vivo. Xenograft and orthotopic models of colon cancer are required to assess the effect of combination therapy on physiologic properties of the tumor microenvironment, including hypoxia, angiogenesis, and proliferation. It is possible that this combination will produce even more impressive anti-tumor effects in a model where HIF-1 and angiogenesis play a critical role in tumor progression. This report provides rationale for the development of CDK4/6 inhibitors as hypoxia-targeting agents and offers preclinical justification for combining palbociclib and irinotecan as a novel approach to treat colon cancer.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.