Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

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.

Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer

“…showed in ER-b/ KRAS mutant mice models that the combination of an ER-b blocker, fulvestrant, with a pan-HER tyrosine kinase inhibitor dacomitinib had a synergistic anti-tumor effect in treating ER-b positive lung cancer. Furthermore, they showed that sequential immunotherapy improved treatment response, suggesting that this combination may provide a novel approach for HR+ KRAS mutated NSCLC ( 44 , 45 ). On further analysis incorporating TMB analysis, we saw a trend towards lower TMB in HR+ NSCLC but we saw a trend towards higher TMB in females in HR+ NSCLC and that HR+ KRAS mutant females specifically had a significantly higher TMB in comparison to males.…”

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

“…A phase 1b, multi-center study of binimetinib plus pemetrexed and cisplatin chemotherapy, followed by the maintenance of binimetinib and pemetrexed for advanced KRAS-mutant NSCLC, reported an ORR of 33%, a median PFS of 5.7 months, and a median OS of 6.5 months, with no unacceptable AEs [ 85 ]. A study found that the sequential triple therapy of anti-PD-1 ICIs sequentially after fulvestrant (anti-estrogen) plus dacomitinib (a pan-HER inhibitor) had the potential for treating KRAS-mutant lung cancer [ 86 ]. In pancreatic cancer, an open-label, phase 2 RCT comparing stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib versus SBRT plus gemcitabine for locally recurrent pancreatic cancer post-operation reported that patients with KRAS mutations as well as high PD-L1 expression had a median OS of 14.9 and 12.8 months, respectively, with the major AEs being increased blood bilirubin and liver impairment [ 87 ].…”

Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments

“…As the same with EGFR-TKIs, other TKIs targeted by KRAS or MET may restrain the expression of PD-L1 as well after sensitive treatments ( 107 , 108 ). After acquiring resistance to ALK inhibitor, PD-L1 expression in ALK-positive NSCLC cell lines and tumors predictably gained an increase in protein levels (including total and surface protein) and mRNA levels ( 109 ).…”