PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D

Abstract

Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.

Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

“…In addition, translational research indicates the potential mechanistic synergy of combining PI3K inhibitors and endocrine therapies, particularly for patients with activating mutations of PIK3CA . 23,24 Taken together, these findings highlight potential treatment benefits of alpelisib, either as a single agent or in combination with endocrine therapy, in PIK3CA -altered ER-positive/HER2-negative breast cancer. Moreover, modest single-agent activity is not uncommon in early studies of targeted agents in a heterogeneous patient population with multiple prior lines of therapy.…”

The PI3K Pathway in Human Disease

“…Inhibition of PI3K was previously reported to stimulate ER-dependent transcription (Bosch et al, 2015). A recent paper provided mechanistic insights into this phenomenon by demonstrating that inhibition of PI3K triggers activation of the lysine methyltransferase, KMT2D, which functions as an enhancer of ER-dependent transcription (Toska et al, 2017). The concept of mutual antagonism involving the PI3K and ER signaling pathways has led to a series of clinical trials testing PI3K inhibitors combined with ER degraders or aromatase inhibitors, as described in other sections of this review.…”

Advances in the management of HER2-positive early breast cancer

“…Activation of the PI3K pathway, either through activating mutations in PIK3CA or through cell surface receptor engagement, causes suppression of ER transcription (Toska et al, 2017). Conversely, inhibition of PI3K signaling activity induces a switch in the transcriptome, moving the tumor toward a more luminal, ER-driven phenotype and increases ER gene expression (Bosch et al, 2015).…”

“…Conversely, inhibition of PI3K signaling activity induces a switch in the transcriptome, moving the tumor toward a more luminal, ER-driven phenotype and increases ER gene expression (Bosch et al, 2015). This change is hypothesized to be due to chromatin remodeling at the ER gene, which occurs in the absence of PI3K signals, allowing for increased transcription of ER RNA (Toska et al, 2017). …”