Reference Detail

Ref Type

Journal Article

PMID

(39121480)

Authors

Loi P, Schade AE, Rodriguez CL, Krishnan A, Perurena N, Nguyen VTM, Xu Y, Watanabe M, Davis RA, Gardner A, Pilla NF, Mattioli K, Popow O, Gunduz N, Lannagan TRM, Fitzgerald S, Sicinska ET, Lin JR, Tan W, Brais LK, Haigis KM, Giannakis M, Ng K, Santagata S, Helin K, Sansom OJ, Cichowski K

Title

Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery			2024 Aug 12		Cancer Discov

URL

Abstract Text

Current treatments for KRAS-mutant colorectal cancers (CRCs) 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 the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	Cetuximab + Encorafenib + Tazemetostat	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Tazverik (tazemetostat) sensitized a colorectal cancer cell line harboring BRAF V600E to treatment with the combination of Braftovi (encorafenib) and Erbitux (cetuximab) in culture, resulting in decreased cell proliferation (PMID: 39121480).	39121480
BRAF V600E	colorectal cancer	sensitive	Encorafenib + Tazemetostat	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Tazverik (tazemetostat) sensitized a colorectal cancer cell line harboring BRAF V600E to Braftovi (encorafenib) treatment in culture, resulting in decreased cell proliferation (PMID: 39121480).	39121480
BRAF V600E	colorectal cancer	sensitive	Tazemetostat + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Tazverik (tazemetostat) sensitized a colorectal cancer cell line harboring BRAF V600E to Mekinist (trametinib) treatment in culture, resulting in decreased cell proliferation (PMID: 39121480).	39121480