DDDR-05 - ERK inhibition increases sensitivity to anti-PD-1 therapy in a mouse model of BRAF mutant melanoma brain metastasis

Saturday, November 19, 2022

1:25 PM – 1:35 PM ET

Location: Ballroom A

Oral Abstract Presenter(s)

Magali de Sauvage, BS (she/her/hers)

Massachusetts General Hospital
Boston, United States

Author(s)

Naema Nayyar, B.S.

University of Massachusetts Medical School
Boston, United States
CT

Consuelo Torrini

Massachusetts General Hospital
Boston, United States
EN

Edwin Nieblas-Bedolla

Massachusetts General Hospital
Boston, United States
Priscilla K. Brastianos, MD

Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School
Boston, United States

Background: Immune checkpoint inhibitors (ICI) have revolutionized the landscape of cancer treatment, including brain metastases. However, only a subset of patients with brain metastases respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, a key regulator of cell processes, are frequently found in brain metastases. LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models. Our objective was to evaluate whether with ERK inhibition (ERKi) can improve the efficacy of ICI in preclinical models of brain metastases.

Methods: We tested sensitivity to LY321 in a BRAFV600E mutant, ICI resistant murine melanoma cell line (D4M) both in vitro and in vivo. To model brain metastases in vivo, we implanted D4M cells subcutaneously with subsequent intracranial implantation three days later. The treatment arms included LY321 and anti-PD-1 combination therapy, single agent therapies, and respective controls. We tested the efficacies of 2-week versus 4-week LY321 treatments, as well as 3-week treatment in an independent experiment.

Results: D4M demonstrates in vitro sensitivity to LY321 (IC₅₀ value of 4.75 µM). Our model demonstrated that LY321 in combination with anti-PD-1 improves both intracranial and extracranial disease control. Increased survival with combination therapy was observed with 3-week and 4-week LY321 administration. While individually, LY321 and anti-PD-1 produced better survival outcomes than control groups, combination therapy significantly outperformed both monotherapies.

Conclusion: Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models. Further investigation is needed to elucidate the mechanisms of this therapeutic approach, and to ultimately determine whether this combination will improve patient outcomes.