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

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 evas...

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Published in:	Cancer research (Chicago, Ill.) Vol. 79; no. 8; pp. 1996 - 2008
Main Authors:	Yokoyama, Yumi, Lew, Erin D, Seelige, Ruth, Tindall, Elizabeth A, Walsh, Colin, Fagan, Patrick C, Lee, Jack Y, Nevarez, Robin, Oh, Joanne, Tucker, Kathleen D, Chen, Marissa, Diliberto, Amy, Vaaler, Heather, Smith, Kristen M, Albert, Amanda, Li, Gary, Bui, Jack D
Format:	Journal Article
Language:	English
Published:	United States 15-04-2019
Subjects:	Adaptive Immunity Animals Apoptosis c-Mer Tyrosine Kinase - antagonists & inhibitors CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell Proliferation Colonic Neoplasms - drug therapy Colonic Neoplasms - immunology Colonic Neoplasms - pathology Female Gene Expression Regulation, Neoplastic - drug effects Humans Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins - antagonists & inhibitors Pyrimidines - pharmacology Quinolines - pharmacology Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Tumor Cells, Cultured Xenograft Model Antitumor Assays
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-18-2022