IMPAKT 2015 News: PI3 Kinase and CDK4/6 Inhibitors Are Highly Active in ER-Positive Breast Cancer

PI3 kinase/mTOR inhibition increases sensitivity of oestrogen receptor-positive breast cancers to CDK4/6 inhibition by palbociclib

The mechanism by which PI3 kinase/mTOR inhibition increases sensitivity of oestrogen receptor (ER)-positive breast cancers to CDK4/6 inhibition is by blocking cell cycle re-entry driven by cyclin D1 and by inducing apoptosis, according to findings presented during the Best Abstracts session at the IMPAKT Breast Cancer Conference held 7–9 May 2015 in Brussels, Belgium.

Lead investigator Maria Teresa Herrera-Abreu, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK and colleagues located in Europe and the USA used compound sensitivity screening to identify drugs that were sensitised with palbociclib, an inhibitor of cell division protein kinase 4 and 6  (CDK4/6), which mediates cell division and proliferation. The team further investigated the mechanisms of this sensitisation both in vitro and in vivo. In this way, an agent that could work synergistically with palbociclib providing increased clinical activity could be uncovered.

The combination efficacy of agents discovered by this screening together with palbociclib was also tested in cell lines that had acquired palbociclib resistance generated by chronic exposure to the drug.

Lasting cell-cycle arrest could not be achieved solely by agents causing CDK4/6 inhibition

CDK4/6 inhibition alone was insufficient to induce a durable cell cycle arrest in ER-positive breast cancer. In fact, it was found that ongoing cell cycle entry was promoted by cyclin D1 binding to CDK2; paradoxically, CDK4/6 inhibition upregulated the expression of cyclin D1.

However, it was also determined that PI3K-AKT-mTOR inhibitors could sensitise ER-positive cell lines to CDK4/6 inhibition by suppressing cyclin D1 expression, thereby effecting a complete loss of RB1 phosphorylation, interrupting the S phase transcription programme, and producing a profound cell cycle arrest.

The investigators noted that apoptosis could be blocked by CDK4/6 inhibition, and that the combination of PI3 kinase and CDK4/6 inhibition could induce apoptosis. Furthermore, this combination was highly efficacious in vivo.

However, sensitivity to palbocicliib was not restored in the cell lines that had acquired resistance to CDK4/6 inhibition by PI3 kinase inhibition.  This held true whether the resistance in the cell lines was due to adaptive loss of CDK4/6 dependence or due to acquired loss of RB1.

Heightened inhibition was achieved using a triple combination of endocrine therapy, CDK4/6 inhibition, and PI3 kinase inhibition, which was shown to be more effective than either doublet.

In summary, combination CDK4/6 and PI3K inhibition is efficacious in vitro and in vivo in ER-positive breast cancer cell lines; PI3K inhibition prolongs cell cycle arrest by preventing cyclin D1 accumulation and RB1 phosphorylation; PI3K inhibition convert the cytostatic effect of palbociclib into cytotoxic; acquired resistance to CDK4/6 inhibition is due to loss of cyclin D1 dependence (RB1 loss or cyclin E1 amplification); and palbociclib resistance cell lines do not benefit from the combination palbociclib/GDC0941. New therapeutic strategies are needed for the treatment of palbociclib resistant cancers.

Dr Lisa Carey of the University of North Carolina, USA, who discussed the study results, said that rational combinations may need to be used early and comprehensively. Cell cycle inhibition erodes and resistance to these drugs is real. CDK2 is implicated in both early and late (acquired) resistance, the finding consistent and implicated by others. Co-targeting PI3K plus CDK4/6 is at least additive but works only against early adaptive resistance, the finding is consistent with work using CDK4/6 inhibitor to circumvent PI3K inhibitor’s resistance. Triple targeting (ER/PI3K/CDK4/6) is best of all. Phase I trial is underway.

Conclusion

The authors concluded that findings from resistant cell lines used in this study demonstrated that the combination of PI3 kinase and CDK4/6 inhibitors is highly active in ER-positive breast cancer, and acts to convert the cytostatic arrest of CDK4/6 inhibition into a profound cytotoxic effect.

Reference

86O PI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis