AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution

Schade A, Perurena N, Yang Y, Rodriguez CL, Krishnan A, Loi P, Mastellone GM, Pilla NF, Watanabe M, Xu Y, Nguyen V, Ota K, Davis RA, Mattioli K, Xiang D, Zoeller JL, Morganti S, Garrido-Castro AC, Tolaney S, Li Z, Barbie DA, Sorger PK, Helin K, Santagata S, Knott SRV, Cichowski K.


Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as at least 70% of TNBCs have PIK3CA/AKT1/PTEN alterations. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease. Here we describe a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor 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 differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Importantly, 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 tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.


Graphical Abstract

EZH2 + AKT inhibitors in TNBC Click to enlarge.

Data Explorations

Data image
HCI-004 PDX tumor: EZH2i/AKTi Combo Treatment Day 1
Data image
HCI-004: PDX tumor EZH2i/AKTi Combo Treatment Day 2
Data image
HCI-004 PDX tumor: EZH2i/AKTi Combo Treatment Day 30
Data image
HCI-004 PDX tumor: Vehicle Treatment

Data Access

Instructions to access data will be posted to the GitHub repository associated with this publication.


This work was supported by a grant from the Cancer Research UK Grand Challenge and the Mark Foundation for Cancer Research to the SPECIFICANCER team (KC) and a DOD BC201085P1 Transformative Breast Cancer Consortium Award (KC). A.S. was supported by an American Cancer Society Postdoctoral Fellowship (PF-22-040-01-ET). N.P. was supported by AACR-AstraZeneca Breast Cancer Research Fellowship (20-40-12-PERU). K.M. was supported by NHGRI F32 #1F32HG012318-01. S.S. was funded by National Cancer Institute grant U54-CA225088 and the BWH President’s Scholar Award. Z.L. was supported by NIH grant R01 CA222560.