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Therapeutic Potential of CDK4/6 Inhibitors in Renal Cell Carcinoma - Beyond the Abstract

One key hallmark of cancer is reliance on sustained replicative potential, and loss of cell cycle control is frequently mediated by alteration to CDK4/6 axis signaling (Figure 1). The cyclin dependent kinases CDK4 and CDK6 are canonically involved in cell cycle checkpoint control with additional roles identified in metabolism and anti-tumor immune response. Specific inhibitors of CDK4/6 are approved for use in breast cancer treatment and are under investigation in numerous other cancers. Regulation of CDK4/6 activity is regulated in part by interaction with endogenous protein inhibitors including p16 (product of CDKN2A gene). Loss of CDKN2A is a frequent event in renal cell carcinoma (RCC) and is associated with worse overall prognosis.1 Many other studies also highlight other alterations to CDK4/6 signaling including loss of tumor suppressive miRNAs which affect expression levels of these important kinases in RCC.2,3

BTA_CDK.png
Figure 1. stabilization and canonical cell cycle function of CDK4. CDK4-cyclin D complexes require assistance of chaperone machinery including Hsp70, Hsp90, and the co-chaperone Cdc37 for assembly and stabilization. The protein p16 is an endogenous inhibitor of CDK4 function. Canonically, CDK4 phosphorylates the tumor suppressor Rb, releasing the transcription factor E2F and thereby allowing progression to the S phase of the cell cycle.

The largest advances in survival with new systemic therapy regimens in RCC have come with the adoption first of tyrosine kinase and mTOR inhibitors followed by immune checkpoint inhibitors, which have become the new gold standard. Interestingly, CDK4/6 inhibitors have been shown to work synergistically with both mTOR inhibitors and immune checkpoint inhibitors in various cancers in preclinical work. This suggests that further investigation of CDK4/6 as a target in RCC and combination of CDK4/6 inhibition with mTOR inhibitors or immune checkpoint blockade may provide a new strategy for treatment optimization in RCC. There is an active trial investigating the combination of the CDK4/6 inhibitor abemaciclib (Verzenio®) with sunitinib (SUTENT®) in metastatic RCC (NCT03905889) following promising preclinical results for combination. Furthermore, there are many ongoing trials with pan-cancer indications for which patients with RCC may be eligible.

Additionally, several studies in RCC models suggest a link in clear cell RCC between VHL loss, HIF activation, and modulation of cell cycle regulation via the CDK4/6-cyclin D axis.4,5 Benefit was seen with the combination of HIF inhibitor and CDK4/6 inhibitor in preclinical models.5 The exact mechanism of how VHL loss affects CDK4/6 signaling, however, has not been fully explored.

Furthermore, there is a need for mechanistic work to unravel the relationship between CDK4/6 dysregulation and other causative driver mutations in RCC in addition to the role of the CDK4/6 signaling axis in driving metabolic alteration. Unraveling these mechanisms will allow for the implementation of rational combination therapies.6 Additionally, mechanisms of resistance to CDK4/6 inhibition need to be explored in RCC specifically, as resistance may be able to be circumvented if understood. As resistance in other cancers can sometimes be mediated by reliance on another CDK such as CDK2 it will also be important to examine separable roles for CDK4, CDK6, and other CDKs as well as specific contributions from each kinase in driving RCC. Further investigation into alternative mechanisms to target CDK4/6 may provide another avenue to combat drug resistance. For example, while the approved inhibitors all target kinase activity we have shown that an alternative strategy is to target the chaperoning and activation of CDK4/6.7 Peptides disrupting CDK4 interaction with its chaperone Hsp90 were able to induce apoptosis in clear cell RCC cell lines. More exploration into these alternative inhibition strategies is warranted.

Taken together, there is strong evidence to suggest that CDK4/6 dysregulation plays a role in RCC and may be a good therapeutic target. Additionally, work in both RCC as well as many other cancers suggests cooperation and synergism between CDK4/6 inhibitors and TKI and mTOR 4 inhibitors as well as immune checkpoint inhibitors that are already used in the treatment of advanced RCC. Further detailed preclinical work specifically in RCC models to dissect the mechanistic role of CDK4/6 in the various histologic subtypes, as well as clinical trials to examine the utility of these inhibitors, are needed

Written by: Rebecca A Sager1,2 and Mehdi Mollapour1,2,3

  1. Department of Urology, SUNY Upstate Medical University, Syracuse, NY
  2. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY
  3. Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY

References:

  1. Ricketts, C. J. et al. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell reports 23, 313-326 e315, doi:10.1016/j.celrep.2018.03.075 (2018).
  2. Xiao, H. et al. MiR-1 downregulation correlates with poor survival in clear cell renal cell carcinoma where it interferes with cell cycle regulation and metastasis. Oncotarget 6, 13201-13215, doi:10.18632/oncotarget.3915 (2015).
  3. Xiao, H. et al. miR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma. Cancer Lett 374, 107-116, doi:10.1016/j.canlet.2016.01.032 (2016).
  4. Bommi-Reddy, A. et al. Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci U S A 105, 16484-16489, doi:10.1073/pnas.0806574105 (2008).
  5. Nicholson, H. E. et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal 12, doi:10.1126/scisignal.aay0482 (2019).
  6. Sager, R. A. et al. Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma. Nature reviews. Urology, doi:10.1038/s41585-022-00571-8 (2022).
  7. Paladino, A. et al. Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions. Chemistry 26, 9459-9465, doi:10.1002/chem.202000615 (2020)

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