Abstract 1762: MALT1 is activated by doxorubicin and mediates therapy resistance in triple-negative breast cancer
Authors: Beecher Maria , Hu Dong , Klei Linda , Little Jack , McAllister-Lucas Linda M. , Lucas Peter C. 
Published: April 2023

Abstract
Background: Breast cancer is the most commonly diagnosed malignancy in American women. The triple-negative breast cancer (TNBC) subtype has among the worst prognosis due to high rates of recurrence and metastasis. Since TNBC lacks targetable receptor proteins, treatment relies upon non-specific chemotherapy, which can become ineffective upon onset of resistance. One potential driver of TNBC treatment resistance is MALT1, the effector component of the CARMA-BCL10-MALT1 signaling complex, which activates NF-κB in multiple cancer cell types, including TNBC. Notably, breast cancer cells demonstrate increased sensitivity to chemotherapies such as doxorubicin and cisplatin when MALT1 is depleted. NF-κB activation has been suggested to promote DNA repair and the MALT1-NF-κB inducible factor, IL-6 has been shown to repress the immunogenic effects of doxorubicin. Hence, we hypothesize that MALT1 is a pharmaceutically targetable driver of TNBC treatment resistance. Mechanistically, we hypothesize that MALT1 promotes chemotherapy resistance by enhancing DNA repair and suppressing immunogenic cell death.
Methods/Results: We analyzed RNAseq and proteomic data from TCGA and CPTAC, respectively, and found that MALT1 is highly expressed in basal breast cancer (a subtype largely composed of TNBC) and its expression level in this context is associated with reduced pathological complete response and survival. With the purpose of evaluating the effect of MALT1 protease inhibition on chemotherapy sensitivity, we first sought to identify TNBC cell lines that were most resistant to doxorubicin using GDSC and CTRP databases. Results indicated that MDA-MB-231, BT20 and HCC1143 were highly resistant. We then performed western blots to assess MALT1 expression and CellTiter-Glo assays to determine the doxorubicin IC50s for these cell lines. Results indicate that MALT1 expression correlates with the degree of doxorubicin resistance among these cell lines. To determine if MALT1 blockade, via siRNA-knockdown or MALT1 protease inhibitor treatment (JNJ-67856633 or MLT-748), increased doxorubicin sensitivity, CellTiter-Glo and Incucyte Caspase-3/7 assays were performed. Findings indicated that MALT1 blockade results in decreased cell viability and increased apoptosis in response to doxorubicin. Mechanistically, MALT1 protease is activated by doxorubicin and MALT1 inhibition increases expression of the immunogenic cell death protein, calreticulin (CRT) in response to doxorubicin.
Conclusions and Future Directions: Initial studies suggest that targeting MALT1 enhances TNBC sensitivity to doxorubicin. We will next assess the effect of MALT1 blockade on DNA repair mechanisms in doxorubicin-treated TNBC cells. Additionally, we will test the role of MALT1 in suppressing immunogenic cell death. Through these studies, we hope to inform new approaches for improving treatment response in TNBC.
Citation Format: Maria Beecher, Dong Hu, Linda Klei, Jack Little, Linda M. McAllister-Lucas, Peter C. Lucas. MALT1 is activated by doxorubicin and mediates therapy resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1762.