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(TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor Yumi Yokoyama1, Erin D

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(TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor Yumi Yokoyama1, Erin D Published OnlineFirst February 5, 2019; DOI: 10.1158/0008-5472.CAN-18-2022 Cancer Tumor Biology and Immunology Research Immuno-oncological Efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor Yumi Yokoyama1, Erin D. Lew1, Ruth Seelige2, Elizabeth A. Tindall3, Colin Walsh1, Patrick C. Fagan1, Jack Y. Lee1, Robin Nevarez1, Joanne Oh1, Kathleen D. Tucker1, Marissa Chen4, Amy Diliberto4, Heather Vaaler4, Kristen M. Smith4, Amanda Albert1, Gary Li1, and Jack D. Bui2 Abstract Expression of the TAM (TYRO3, AXL, MER) family of macrophages, and activation of natural killer cells. RXDX- þ receptor tyrosine kinases (RTK) has been associated with 106 proportionally increased intratumoral CD8 Tcellsand cancer progression, metastasis, and drug resistance. In T-cell function as indicated by both IFNg production and immune cells, TAM RTKs can dampen inflammation in LCK phosphorylation (pY393). RXDX-106 exhibited its favor of homeostatic wound-healing responses, thus poten- effects via direct actions on TAM RTKs expressed on intra- tially contributing to the evasion of cancer cells from tumoral macrophages and dendritic cells, leading to indirect immune surveillance. Here we characterize the small-mol- activation of other immune cells in the tumor. RXDX-106 ecule RXDX-106 as a selective and potent pan-TAM RTK also potentiated the effects of an immune checkpoint inhib- inhibitor with slow dissociation kinetics and significant itor, a-PD-1 Ab, resulting in enhanced antitumor efficacy antitumor activity in multiple syngeneic tumor models. and survival. Collectively, these results demonstrate the Expression of AXL and MER on both immune and tumor capacity of RXDX-106 to inhibit tumor growth and progres- cells increased during tumor progression. Tumor growth sion and suggest it may serve as an effective therapy against inhibition (TGI) following treatment with RXDX-106 was multiple tumor types. observed in wild-type mice and was abrogated in immuno- deficientmice,suggestingthattheantitumoractivityof Significance: The pan-TAM small-molecule kinase inhibi- RXDX-106 is, in part, due to the presence of immune cells. tor RXDX-106 activates both innate and adaptive immunity to RXDX-106–mediated TGI was associated with increased inhibit tumor growth and progression, indicating its clinical tumor-infiltrating leukocytes, M1-polarized intratumoral potential to treat a wide variety of cancers. promising immunotherapies for cancer (2). Antibodies that block Introduction þ CTLA-4, PD-1, or PD-L1 show clinical efficacy by boosting CD4 Immune checkpoints can block cell expansion/activation, þ Th cells or by restoring activity of exhausted CD8 T cells, abrogate the immune response, and initiate return to homeosta- respectively (3, 4). Nevertheless, the response rate to checkpoint sis, but tumors have pathologically coopted these pathways to blockade remains 30% for many cancers, in part, due to the restrict effective antitumor responses (1). Targeted inhibition of suppressive milieu in the tumor microenvironment (TME) stem- these negative regulatory checkpoints has emerged as viable and ming from suppressive innate immune cells, including myeloid- derived suppressor cells (MDSC; ref. 5), M2-like macrophages (6), 1Translational Research, Ignyta, Inc., San Diego, California. 2Department of dysfunctional dendritic cells (DC; ref. 7), and natural killer (NK) Pathology, University of California, San Diego, La Jolla, California. 3Computa- cells (8). Presumably, therapies that activate/polarize the innate tional Biology, Ignyta, Inc., San Diego, California. 4Diagnostics, Ignyta, Inc., San immune system could synergize with checkpoint inhibitors to Diego, California. boost antitumor effects of the adaptive immune system (9). Note: Supplementary data for this article are available at Cancer Research One group of checkpoint molecules that regulate innate immu- Online (http://cancerres.aacrjournals.org/). nity are the TAM RTKs–TYRO3, AXL, and MER, which are broadly Y. Yokoyama, E.D. Lew, and R. Seelige contributed equally to this article. expressed on several immune cell lineages, including macro- phages, DCs, and NK cells (10). With their ligands, GAS6 and E.A. Tindall and C. Walsh contributed equally to this article. PROS1, TAM RTKs help to resolve inflammatory signals and À À J.D. Bui and G. Li contributed equally to this article. participate in wound healing. In Mertk / mice, inefficient clear- Corresponding Authors: Jack D. Bui, University of California, San Diego, 9500 ance of apoptotic cells by monocyte-derived and epithelial cells, Gilman Drive, La Jolla, CA 92093-0612. Phone: 858-534-3890; Fax: 858-822- a process dependent on MER activation by GAS6 or PROS1 5580; E-mail: [email protected]; and Erin D. Lew, Ignyta, Inc., San Diego, CA 92121. complexed with externalized phosphatidylserine (PtdSer) on Phone: 203-543-8260; Fax: 858-822-5580; E-mail: [email protected]. apoptotic bodies (11, 12), leads to aberrant accumulation of doi: 10.1158/0008-5472.CAN-18-2022 apoptotic material, instigating inflammation. MER also sup- Ó2019 American Association for Cancer Research. presses the M1 macrophage/pro-inflammatory cytokine response 1996 Cancer Res; 79(8) April 15, 2019 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst February 5, 2019; DOI: 10.1158/0008-5472.CAN-18-2022 Immuno-oncologic Effect of RXDX-106, a TAM RTK Inhibitor while enhancing the M2 macrophage/anti-inflammatory produc- and animals were dosed orally every day. Female C57BL/6, tion (13–15). On antigen-presenting cells (APC), Toll-like recep- BALB/c, athymic nude, BALB/c nude, SCID Beige, and CD45.1 tor (TLR) signaling upregulates AXL, which complexes with the C57BL/6 mice between 6 and 7 weeks of age were ordered from type-I interferon receptor (IFNAR1), eliciting negative feedback Charles River. C57BL/6 MMTV-PyMT (PyMT) female mice were þ on further TLR signaling (16). In addition, activated CD8 T cells bred in-house [University of California, San Diego (UCSD), San upregulate PROS1 and externalize PtdSer; this complex, in turn, Diego, CA]. CD45.1.2 C57BL/6 mice were a kind gift from Dr. stimulates TAM receptors on APCs, reducing APC activity (17). John Chang (University of California, San Diego, San Diego, CA). À À À À Furthermore, TAM triple knockout mice (TAM TKO), although Bones from Axl / Mertk / (AM) double knockout (AMdKO) gestationally viable, develop chronic inflammation and systemic mice were a kind gift from Dr. Greg Lemke (Salk Institute, La Jolla, autoimmunity, multiple organ defects, and massive lymphopro- CA). Animal experiments were conducted in accordance with liferative disease due to overactivation of the innate immune guidelines established by the Explora Biolabs Institutional Ani- system and failure to clear apoptotic debris, leading to engage- mal Care Use Committee (IACUC; Ignyta ACUP# EB15-050). ment of the adaptive immune response (18). Cells (1 Â 106 cells/mouse, unless otherwise indicated) were Abnormal overexpression of TAM RTKs and/or GAS6 has been implanted subcutaneously on the right flank of each mouse. documented in a wide range of malignancies (14, 19, 20). In Tumor-bearing mice were randomized and treated orally every contrast to its perceived inhibition of immune cell signaling, TAM day with vehicle or RXDX-106 at 30 mg/kg or at indicated doses. receptor activation in tumor cells promotes survival and tumor- For studies with NIH3T3 cells expressing TYRO3, AXL, and MER, igenicity (21, 22). In the TME, where resources such as oxygen and SCID/Beige animals were inoculated and treated on the indicated nutrients are scarce, TAM RTK signaling may be critical in providing day with RXDX-106 orally every day when mean tumor volume survival cues (20, 23), while promoting chemoresistance, colony- reached approximately 140, 60, and 150 mm3, respectively. forming potential, invasion/motility, and induction of epithelial- For TGI combination studies with anti-PD-1 antibody, MC38 to-mesenchymal transition (EMT; refs. 14, 20, 21, 24). Thus, TAM and CT26 cells were implanted subcutaneously in the right flank RTKs may both dampen inflammation and activate/promote of C57BL/6 and BALB/c mice, respectively. Mice were randomized cancer cell progression, encouraging development of therapeutic and treated when tumors reached 130 mm3. Animals were treated agents that inhibit TAM receptors for cancer immunotherapy. with 30 mg/kg RXDX-106 (orally every day) Æ antibodies (intra- The frequent observation of 2 TAM RTKs coexpressed on peritoneally, two times/week; 10 mg/kg anti-PD-1 antibody or rat immune cells (25) and the normal phenotype of single- or IgG2a antibodies). Survival was monitored for a maximum dura- double-TAM knockout mice in contrast to the autoinflammatory tion of 60 days or until tumor volume reached 2,000 mm3. Isotype and autoimmune phenotype of the TAM TKO (18), suggests a antibody had no effect on tumor growth. For immunophenotyp- redundancy in TAM receptor activity in innate immune cells. ing and RNA-seq combination study, animals were treated for 7 Indeed, in response to selective TAM RTK agents (i.e., anti- days with either vehicle or RXDX-106 (orally every day) Æ anti- AXL–specific inhibition), cancer cells upregulate other TAM RTK bodies (anti-PD-1 antibody or rat IgG2a antibodies (10 mg/kg) family members as a mechanism of resistance (26). In this report, intraperitoneally 2Â/week. PyMT mice were treated orally every we document the characterization of RXDX-106, a novel small- day with vehicle or RXDX-106 at 30 mg/kg at tumor onset. molecule inhibitor of all three TAM RTKs. RXDX-106 blocked TAM RTKs on both tumor and immune cells, both in vitro and Generation of bone marrow chimeric mice in vivo. This activity reduced tumor progression, even in tumor Eight-week-old female CD45.1 mice were irradiated with 1,000 cells that do not respond to TAM RTK inhibition, suggesting that cGy and intravenously injected with 5 Â 106 bone marrow (BM) RXDX-106 activated antitumor immunity. Indeed, RXDX-106 cells from WT CD45.2 or AMdKO CD45.2, respectively.
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