Abstract
Triple-negative breast cancers (TNBCs) are heterogeneous and aggressive, with high mortality rates. TNBCs frequently respond to chemotherapy, yet many patients develop chemoresistance. The molecular basis and roles for tumor cell–stromal crosstalk in establishing chemoresistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient–derived xenografts (PDXs) established before and after the development of chemoresistance. Interestingly, the chemoresistant model acquired a distinct KRASQ61R mutation that activates K-Ras. The chemoresistant KRAS-mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically, KRAS-mutant PDXs exhibited increased redox ratios and decreased activation of AMPK, a protein involved in responding to metabolic homeostasis. Additionally, the chemoresistant model exhibited increased immunosuppression, including expression of CXCL1 and CXCL2, cytokines responsible for recruiting immunosuppressive leukocytes to tumors. Notably, chemoresistant KRAS-mutant tumors harbored increased numbers of granulocytic myeloid-derived suppressor cells (gMDSCs). Interestingly, previously established Ras/MAPK-associated gene expression signatures correlated with myeloid/neutrophil-recruiting CXCL1/2 expression and negatively with T cell–recruiting chemokines (CXCL9/10/11) across patients with TNBC, even in the absence of KRAS mutations. MEK inhibition induced tumor suppression in mice while reversing metabolic and immunosuppressive phenotypes, including chemokine production and gMDSC tumor recruitment in the chemoresistant KRAS-mutant tumors. These results suggest that Ras/MAPK pathway inhibitors may be effective in some breast cancer patients to reverse Ras/MAPK-driven tumor metabolism and immunosuppression, particularly in the setting of chemoresistance.
Highlights
Triple-negative breast cancer (TNBC) is a unique clinical subtype of breast cancer characterized by uniform lack of estrogen receptor and progesterone receptor expression and the absence of human epidermal growth factor receptor amplification
Our work has focused on the study of paired breast cancer patient– derived xenografts (PDXs) before and after the development of chemotherapy resistance to identify targetable, KRAS mutant–associated signaling mechanisms that promote tumor progression and alter the tumor immune microenvironment
3D Biology analysis of PDX tumors treated with a combination of chemotherapy and MEKi identified immune and metabolic pathways that were inhibited by MEKi treatment
Summary
Triple-negative breast cancer (TNBC) is a unique clinical subtype of breast cancer characterized by uniform lack of estrogen receptor and progesterone receptor expression and the absence of human epidermal growth factor receptor amplification. TNBC is characterized by diverse chromosomal aberrations and frequent loss of tumor suppressor p53 functions but infrequent druggable mutations. This genomic instability contributes to its heterogeneity and the perception that TNBC is a diverse collection of malignancies rather than a unique molecular entity [1]. The Ras/ MAPK pathway has been shown to be primarily activated in breast cancer via loss of negative regulation [6, 7]. The development of targeted Ras/MAPK therapeutics in TNBC requires additional study on which tumors are likely to respond, what is the most effective way to incorporate Ras/MAPK inhibitors (i.e., MEK inhibitors; MEKi) into therapy, and which molecular phenotypes can be effectively targeted
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