CARM1-Mediated MAP2K4 Methylation Potentiates the Oncogenic Functions of MAP2K4 and Constitutes a Targetable Dependency in Triple-Negative Breast Cancer

Abstract The arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1) is amplified/overexpressed in a variety of cancers, including triple-negative breast cancer (TNBC), spurring the interest of developing CARM1 inhibitors (CARM1i). In this study, we discovered that CARM1i treatment leads to elevated CARM1 levels as well as activation of AKT, which could result in long-term treatment resistance in breast cancer cells. CARM1 methylated MAP2K4 at arginine 58 in TNBC, and methylated-MAP2K4 localized to the nucleus and potentiated the proliferation- and metastasis-promoting functions of MAP2K4 via activation of JNK signaling. Inhibition of MAP2K4 by CARM1i led to AKT activation, which was abrogated by treatment with a PI3K inhibitor. Combining CARM1i and PI3K inhibitor elicited synergistic anticancer effects in TNBC cell lines, organoids, and patient-derived xenografts. This study demonstrates that, through inhibiting MAP2K4 methylation, CARM1i abrogates the feedback loop of MAP2K4 and PI3K signaling, supporting treatment with CARM1i as a therapeutic approach to improve the sensitivity of TNBC to PI3Ki. Significance: CARM1 mediates MAP2K4 activation and cross-talk with PI3K/AKT signaling, providing potential combination approaches for treating triple-negative breast cancer and explains the paradoxical role of MAP2K4 in ER+ and triple-negative breast cancer.