CDK4/6 Blockade Improves the Efficacy of PI3K Inhibition in Breast Cancer

Activation of PI3K signaling is a common feature of many breast cancers and frequently occurs via mutations in the PIK3CA oncogene encoding the PI3K p110α subunit. However, PI3K inhibitors have shown only modest clinical efficacy, and patients with PIK3CA-mutant tumors often develop acquired resistance. Recent studies have shown that dual inhibition of mTOR complex (mTORC) and PI3K is effective in PIK3CA-mutant cancer, indicating that mTORC activation contributes to PI3K inhibitor resistance. To identify additional therapeutic strategies to enhance the sensitivity of PI3K inhibitors, Vora and colleagues performed a combinatorial drug screen in PIK3CA-mutant, PI3K inhibitor–resistant breast cancer cell lines. Intriguingly, concomitant inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6), which function downstream of mTORC1, broadly increased PI3K inhibitor sensitivity in PIK3CA-mutant cells with acquired and intrinsic PI3K inhibitor resistance and synergistically reduced cell viability. The efficacy of CDK4/6 inhibition was mediated, in part, by activation of the tumor suppressor RB; single-agent PI3K blockade failed to inhibit CDK4/6–cyclin D1 activity downstream of mTORC1 in PI3K inhibitor–resistant cell lines, which exhibited persistent RB phosphorylation. Maintenance of RB phosphorylation was also correlated with PI3K inhibitor resistance in patients, including both those classified as nonresponders and those that developed resistant tumors, suggesting that phosphorylated RB may represent a biomarker of clinical response to PI3K inhibitors. Importantly, combined treatment with PI3K and CDK4/6 inhibitors was well tolerated, suppressed AKT activity and RB phosphorylation, and induced xenograft tumor regression in PIK3CA-mutant breast cancer models. These findings support further investigation of this combination as a means to overcome PI3K inhibitor resistance in patients with PIK3CA-mutant breast cancer.

Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136–49.

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