Reference Detail

Ref Type

Journal Article

PMID

(34158350)

Authors

Zhang D, Hou Z, Aldrich KE, Lockwood L, Odom AL, Liby KT

Title

A Novel Nrf2 Pathway Inhibitor Sensitizes Keap1-Mutant Lung Cancer Cells to Chemotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	9	2021 Sep	1692-1701	Mol Cancer Ther

URL

Abstract Text

The nuclear factor erythroid-2-related factor 2 (Nrf2)-Keap1-ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

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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
MSU38225	MSU38225	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MSU38225		MSU-38225\|MSU 38225		MSU38225 is an Nrf2 inhibitor, potentially inhibiting Nrf2 transcriptional activity and cancer cell growth (PMID: 34158350).

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
KEAP1 inact mut	lung adenocarcinoma	sensitive	MSU38225	Preclinical - Cell culture	Actionable	In a preclinical study, MSU38225 inhibited Nrf2 transcriptional activity and downstream pathway activation, increased Nrf2 degradation, and inhibited growth of lung cancer cells harboring a KEAP1 inactivating mutation in 2D and 3D culture (PMID: 34158350).	34158350
KEAP1 inact mut	lung adenocarcinoma	sensitive	Carboplatin + MSU38225	Preclinical - Cell line xenograft	Actionable	In a preclinical study, MSU38225 and Paraplatin (carboplatin) combination treatment synergistically inhibited growth of a lung cancer cell line harboring a KEAP1 inactivating mutation in culture and slowed tumor growth in a cell line xenograft model compared to vehicle or Paraplatin (carboplatin) alone (PMID: 34158350).	34158350
KEAP1 inact mut	lung adenocarcinoma	sensitive	Fluorouracil + MSU38225	Preclinical - Cell culture	Actionable	In a preclinical study, MSU38225 and Adrucil (fluorouracil) combination treatment inhibited growth of a lung cancer cell line harboring a KEAP1 inactivating mutation in culture (PMID: 34158350).	34158350