CDK6 Could Be a Key Factor for Efficacy of CDK4/6 Inhibitors and the Hormone Sensitivity Following Acquired Resistance

Conference Correspondent  - SABCS 2017 - Breast Cancer

CDK4/6 inhibitors have received FDA breakthrough therapy designation as first-line treatment for patients with advanced, estrogen-receptor (ER)-positive breast cancer. A challenge to the benefit offered by CDK4/6 inhibitors, however, is acquired resistance to the drugs. Thus, there is a need to identify a biomarker to understand drug sensitivity to CDK4/6 inhibitors and its alteration after acquired resistance.

To evaluate the efficacy of CDK4/6 inhibitors, the authors assessed IC50 of ribociclib in several cell lines. Luminal cell lines (MCF-7, T-47D) exhibited lower ribociclib IC50 than HER2-positive (SK-BR-3) and triple-negative cell lines (MDA-MB-231, BT-20). Immunoblot analysis of luminal cell lines showed significantly lower levels of CDK6 compared with others. CDK6-transfected MCF-7 by means of an expression vector reduced the sensitivity equivalent to MDA-MB-231, not only to ribociclib but also to palbociclib and abemaciclib. Protein levels of ER-alpha and fulvestrant sensitivity in CDK6-transfected MCF-7 remained unchanged.

Subsequently, the efficacy of ribociclib was assessed in hormone-resistant cell lines. Estrogen deprivation‒resistant (EDR) cells (EDR1: ER-positive; EDR2: ER-negative) and fulvestrant-resistant cells (loss of ER expression) established from MCF-7 maintained ribociclib sensitivity to the same degree as MCF-7. No marked difference in IC50 was observed between EDR1/2 and MFR, and CDK6 expression was comparable to that seen with MCF-7. These results suggest that a high level of CDK6 expression may reduce sensitivity to CDK4/6 inhibitors, and that CDK4/6 inhibitors may be more effective in tumors expressing lower levels of CDK6 compared with those expressing higher CDK6 levels, independent of hormone sensitivity.

To further understand the characteristics in acquired resistance, ribociclib-resistant cell lines (RIBR1/2) were established from EDR1 by long-term culture with ribociclib; these cell lines demonstrated lower levels of p21, p27, and ER-alpha by immunoblot analysis. Cell growth in EDR1 was promoted by estrogen addition, whereas RIBR did not show this effect. Furthermore, the ER activity of RIBR was markedly decreased, and mRNA levels of the ER target genes PgR and EGR3 were also decreased, thereby losing the responsiveness to tamoxifen and fulvestrant. On the other hand, PI3K inhibitors and mTOR inhibitors suppressed cell growth in RIBR to the same extent as in EDR1, suggesting that RIBR has reduced ER dependence and remains reliant on the PI3K/Akt/mTOR pathway for cell growth.

The authors concluded that CDK6 may be a useful biomarker for acquired resistance to CDK4/6 inhibition in patients with ER-positive breast cancer, as shown by the finding that a low level of CDK6 expression is positively correlated with the efficacy of CDK4/6 inhibitors. Moreover, the inhibition of the PI3K/Akt/mTOR pathway in the patient population that develops resistance to CDK4/6 inhibitors may be a reasonable therapeutic target.

Iida M, et al. SABCS 2017. Abstract P6-04-02.

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Last modified: December 10, 2017