The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.
Oncogenic signaling pathways both directly and indirectly regulate anabolic metabolism, and this is required for tumor growth. Targeted therapies that inhibit oncogenic signaling have dramatic impacts on cellular metabolism. However, it is not known whether the acquisition of resistance to these therapies is associated with -or driven by -alterations in cellular metabolism. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during residual disease, and after tumor recurrence. We found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during residual disease and tumor recurrence, and NRF2 was both sufficient to promote tumor recurrence, and necessary for recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors induced metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. Finally, this NRF2-driven metabolic state rendered recurrent tumor cells sensitive to glutaminase inhibition, suggesting that NRF2-high recurrent tumors can be therapeutically targeted. Together, these data provide evidence that NRF2-driven metabolic reprogramming is required for breast cancer recurrence following oncogene inhibition. SignificanceAlthough tumor recurrence is the leading cause of mortality in breast cancer, the cellular properties that allow tumor cells to evade therapy and form recurrent tumors remain largely uncharacterized. Similarly, very little is known about how tumor metabolism changes following therapy, or whether alterations in cellular metabolism drive tumor recurrence. In this study, we identify the antioxidant transcription factor NRF2 as a critical positive regulator of breast cancer recurrence. We find that NRF2-dependent metabolic reprogramming is both sufficient and required to promote tumor recurrence. Additionally, we demonstrate that the NRF2-driven metabolic state renders recurrent tumors sensitive to glutaminase inhibitors, suggesting a novel therapeutic approach for the treatment of recurrent breast cancer. KeywordsNRF2, ROS, Tumor metabolism, Residual disease, Breast cancer recurrence, Her2 ! 3!
1045 Background: In patients (pts) with stable or no extracranial disease (ECD) presenting with breast cancer brain metastases (BCBrMs), current guidelines recommend pts receive local therapy with radiation +/- surgery, without changing systemic therapy. However, preliminary studies suggest that pts with isolated HER2+ BCBrM without ECD have inferior overall survival (OS) compared to pts with concurrent ECD. Our study further explores the implications of ECD status on intracranial progression free survival (iPFS) and OS. Methods: Retrospective analysis was performed on data from 153 pts diagnosed with initial HER2+ BCBrM who received CNS radiation at Duke between 2008 and 2020. Demographics, dates of metastatic and BCBrM diagnosis, ECD status at first CNS event, systemic therapy, and outcomes were collected. The primary endpoint was iPFS defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known contact. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS event. Results: In this cohort of 153 pts with HER2+ BCBrMs undergoing CNS radiation, > 70% of pts with known ECD status had controlled systemic disease: either no ECD (27%) or stable/responding disease (44%). 64% of pts’ tumors were ER+. Median age was 50 years (range 24 – 75). Most pts (59%) developed first CNS event during adjuvant or 1st/2nd line metastatic therapy. CNS radiation treatment included 48% of pts receiving SRS only, 9% WBRT only, and 43% SRS and WBRT. All pts with no ECD presented with isolated BCBrMs as first metastatic disease. Among pts with known ECD status, OS from initial metastatic disease to death was markedly worse for pts with isolated brain metastases or no ECD (median = 28.4m, 95% CI: 18.1 to not reached) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 40.5 to 65.0; and 68.1m, 95% CI: 55.2 to 85.7, respectively; log-rank p = 0.004). OS from first CNS involvement to death was significantly worse for pts with progressive ECD (17.8m, 95% CI: 13.7 to 28.8) versus stable/responding (36.6m, 95% CI: 29.7 to 45.2) or no ECD (28.4m, 95% CI: 18.1 to not reached; log-rank p = 0.008). iPFS did not differ statistically among subgroups of pts with known ECD status: progressive ECD (median = 7.7m), no ECD (8.3m), or stable/responding ECD (11.2m) (log-rank p = 0.15). Conclusions: Overall survival in pts with HER2+ isolated BCBrM was markedly inferior to that of pts with progressive or stable/responding ECD. Studies investigating initiation of brain penetrable HER2-targeted therapies earlier in the disease course of isolated HER2+ BCBrMs pts are warranted.
PurposeCurrent guidelines for patients with HER2+ breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2+ BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after rst incidence of HER2+ BCBrM and radiation. MethodsA retrospective analysis was performed of 153 patients diagnosed with initial HER2+ BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2020. The primary endpoint was iPFS de ned as time from rst CNS radiation treatment to intracranial progression or death. OS was de ned as time from rst CNS radiation or rst metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM de ned ECD status. ResultsIn this cohort, >70% of patients had controlled ECD with either isolated intracranial relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median=28.4m) compared to those with progressive or stable/responding ECD (48.8m and 68.1m, respectively, p=0.0035). OS from rst CNS radiation to death was signi cantly worse for patients with progressive ECD (17.8m) versus stable/responding (36.6m) or isolated intracranial relapse (28.4m, p=0.008). iPFS did not differ statistically. ConclusionOS in patients with HER2+ isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain penetrable HER2-targeted therapies earlier in the disease course of isolated HER2+ intracranial relapse patients are warranted.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.