Immuno-oncological Efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor

Autor: Marissa Chen, Jack Y. Lee, Yumi Yokoyama, Colin Walsh, Heather Vaaler, Patrick Fagan, Amy Diliberto, Jack D. Bui, Elizabeth A. Tindall, Joanne Oh, Amanda Albert, Robin Nevarez, Erin D. Lew, Ruth Seelige, Kathleen D. Tucker, Gary Li, Kristen M. Smith
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Mice
Nude
Apoptosis
Inflammation
Adaptive Immunity
CD8-Positive T-Lymphocytes
Receptor tyrosine kinase
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Proto-Oncogene Proteins
Tumor Cells
Cultured
medicine
Animals
Humans
Protein Kinase Inhibitors
Cell Proliferation
Mice
Inbred BALB C
c-Mer Tyrosine Kinase
biology
Chemistry
Kinase
Macrophages
Receptor Protein-Tyrosine Kinases
Acquired immune system
Xenograft Model Antitumor Assays
Axl Receptor Tyrosine Kinase
Gene Expression Regulation
Neoplastic
Killer Cells
Natural
Mice
Inbred C57BL
Pyrimidines
030104 developmental biology
Oncology
Tumor progression
030220 oncology & carcinogenesis
Colonic Neoplasms
Cancer cell
Quinolines
Cancer research
biology.protein
Female
medicine.symptom
CD8
Zdroj: Cancer Research. 79:1996-2008
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.can-18-2022
Popis: Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106–mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types. Significance: The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.
Databáze: OpenAIRE
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