PMID- 35008514
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20220131
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 1
DP  - 2021 Dec 22
TI  - Targeting the ERbeta/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the 
      Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy.
LID - 10.3390/ijms23010081 [doi]
LID - 81
AB  - High ERbeta/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.
FAU - Almotlak, Abdulaziz A
AU  - Almotlak AA
AD  - Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin 
      Faisal University, Dammam 34212, Saudi Arabia.
FAU - Farooqui, Mariya
AU  - Farooqui M
AD  - Department of Pharmacology, Masonic Cancer Center, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Soloff, Adam C
AU  - Soloff AC
AD  - Department of Cardiothoracic Surgery, UPMC Hillman Cancer Center, University of 
      Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
FAU - Siegfried, Jill M
AU  - Siegfried JM
AD  - Department of Pharmacology, Masonic Cancer Center, University of Minnesota, 
      Minneapolis, MN 55455, USA.
AD  - Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, 
      University of Pittsburgh, Pittsburgh, PA 15213, USA.
FAU - Stabile, Laura P
AU  - Stabile LP
AUID- ORCID: 0000-0002-1822-2707
AD  - Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, 
      University of Pittsburgh, Pittsburgh, PA 15213, USA.
LA  - eng
GR  - no grant number/University of Minnesota Foundation through a donation from the 
      State of Minnesota Eagles of the Masonic Cancer Center/
GR  - no grant number/Alice and Frederick Stark Endowed Chair in Pharmacology/
GR  - no grant number/A Breath of Hope Lung Foundation Tona Vives Award/
GR  - no grant number/Hillman Fellows for Innovative Cancer Research Program/
GR  - no grant number/Imam Abdulrahman Bin Faiscal University fellowship program in 
      conjunction with the Saudi Arabian Cultural Mission (SACM) to the USA/
PT  - Journal Article
DEP - 20211222
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (KRAS protein, human)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Quinazolinones)
RN  - 5092U85G58 (dacomitinib)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/drug effects/immunology
MH  - Carcinogenesis/genetics/immunology
MH  - Cell Line, Tumor
MH  - Estrogen Receptor beta/*genetics/immunology
MH  - Female
MH  - Humans
MH  - Immunotherapy/methods
MH  - Lung Neoplasms/*genetics/immunology/therapy
MH  - Lymphocytes, Tumor-Infiltrating/drug effects/immunology
MH  - Macrophages/drug effects/immunology
MH  - Mice
MH  - Oncogenes/genetics/immunology
MH  - Programmed Cell Death 1 Receptor/genetics
MH  - Proto-Oncogene Proteins p21(ras)/*genetics/immunology
MH  - Quinazolinones/pharmacology
MH  - Receptor, ErbB-2/*genetics/immunology
MH  - Tumor Microenvironment/*genetics/immunology
PMC - PMC8745184
OTO - NOTNLM
OT  - ER
OT  - HER
OT  - KRAS
OT  - NSCLC
OT  - PAM50
OT  - TME
OT  - anti-PD-1
OT  - immunotherapy
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/12 06:00
MHDA- 2022/02/01 06:00
PMCR- 2021/12/22
CRDT- 2022/01/11 01:02
PHST- 2021/09/29 00:00 [received]
PHST- 2021/12/13 00:00 [revised]
PHST- 2021/12/20 00:00 [accepted]
PHST- 2022/01/11 01:02 [entrez]
PHST- 2022/01/12 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2021/12/22 00:00 [pmc-release]
AID - ijms23010081 [pii]
AID - ijms-23-00081 [pii]
AID - 10.3390/ijms23010081 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Dec 22;23(1):81. doi: 10.3390/ijms23010081.