Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is
Abdulaziz A Almotlak1, Mariya Farooqui2, Adam C Soloff3
1Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia.
Abstract:
High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.
Insights
Combining fulvestrant and dacomitinib shows promise for KRAS mutant lung cancer. This therapy impacts the tumor microenvironment and immune cells, suggesting sequential anti-PD-1 antibody administration enhances anti-tumor effects.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Estrogen receptor beta (ERβ) and human epidermal growth factor receptor (HER) signaling drive aggressive lung tumor biology.
- Previous research demonstrated synergistic anti-tumor effects of fulvestrant and dacomitinib in immunocompromised models of KRAS mutant lung adenocarcinoma.
- The impact of this combination therapy on the tumor microenvironment (TME) remained unexplored.
Purpose of the Study:
- To investigate the effects of fulvestrant and dacomitinib on immune cells, specifically murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells.
- To evaluate the in vivo efficacy of the fulvestrant and dacomitinib combination in a KRAS mutant syngeneic lung adenocarcinoma model.
- To explore the potential of combining this therapy with immune checkpoint inhibitors.
Main Methods:
- Evaluation of fulvestrant and dacomitinib effects on isolated BMDMs and CD8+ T cells.
- Assessment of combination therapy efficacy in the FVBW-17 syngeneic KRAS mutant lung adenocarcinoma model.
- In vivo studies using subcutaneous flank and lung metastasis models, including combination with anti-PD-1 antibody.
Main Results:
- The combination synergistically inhibited FVBW-17 cell proliferation but negatively impacted immune cells, reducing CD8+ T cell activity and macrophage phagocytosis, and inducing PD-1 expression.
- Dacomitinib was identified as the primary contributor to these immune effects, linked to downregulation of Src family kinases and Syk.
- In vivo, the combination induced an inflamed TME with increased myeloid and CD8+ T cells and enhanced PD-1 expression. Sequential anti-PD-1 administration demonstrated superior tumor inhibition compared to concomitant therapy.
Conclusions:
- The combination of fulvestrant and dacomitinib affects the tumor microenvironment and immune cells, necessitating strategies to overcome immune suppression.
- Sequential administration of anti-PD-1 antibody with fulvestrant and dacomitinib shows significant synergistic anti-tumor activity in preclinical lung cancer models.
- This sequential triple therapy strategy holds potential for treating refractory lung cancers, including KRAS mutant adenocarcinoma.
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