Anjana Krishnan

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3–6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit. AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.

Abstract Current treatments for KRAS-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress Wingless and Int-1 (WNT)-driven transcription and drive colorectal cancers into a more differentiated cell state by inducing the Groucho/transducin-like enhancer corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the proapoptotic protein BCL2 modifying factor (BMF), which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, by blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant colorectal cancers and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis. Significance: Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.

<p>Extended data related to Figure 1.</p>

<div>Abstract<p>Current treatments for <i>KRAS</i>-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway inhibitors and promote dramatic tumor regression <i>in vivo</i>. Together these agents cooperatively suppress Wingless and Int-1 (WNT)-driven transcription and drive colorectal cancers into a more differentiated cell state by inducing the Groucho/transducin-like enhancer corepressor, <i>TLE4</i>, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the proapoptotic protein BCL2 modifying factor (BMF), which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, by blocking differentiation, or by ablating <i>BMF</i> expression. Collectively, these studies reveal a new therapeutic approach for treating <i>KRAS-</i>mutant colorectal cancers and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.</p>Significance:<p>Combined EZH2 and RAS pathway inhibitors kill <i>KRAS-</i>mutant colorectal cancer cells and promote durable tumor regression <i>in vivo</i>. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.</p></div>

<p>Extended data related to Figure 5.</p>