RXDX-106 / Roche, Daiichi Sankyo - LARVOL DELTA

Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction. (PubMed, J Dent Res) - "Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury."

Journal • Inflammation • AXL • MERTK

Integrated proteomics-based physical and functional mapping of AXL kinase signaling pathways and inhibitors define its role in cell migration. (PubMed, Mol Cancer Res) - "Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT and migration/invasion of these cells without reducing their viability, while Bemcentinib exerts AXL-independent phenotypic effects on viability...However, a unique vulnerability was identified in one resistant clone, wherein combination of Bemcentinib and Erlotinib inhibited cell viability and signaling...Cell lines have a wide range of AXL expression, with basal activation detected rarely. Implications: Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL-complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy."

Journal • Lung Cancer • Oncology • Solid Tumor • AXL • EGFR

Mechanistic and pharmacodynamic characterization of the immuno-oncological activity of RXDX-106, a novel TYRO3, AXL, and MER (TAM) inhibitor in clinical development (AACR 2018) - "In summary, RXDX-106 has the potential to restore and enhance immune function by modulating the local immunosuppressive TME. The unique mechanism of activating both innate and adaptive immunity, and regulating cross-talk between immune cells and tumor cells, supports clinical evaluation of RXDX-106 as an immunomodulatory agent for the treatment of a variety of cancers."

Clinical • IO Biomarker • PK/PD data • Oncology

[VIRTUAL] Erlotinib resistance via a persister bottleneck results in mixed expression of EGFR T790M and EMT-like state with high AXL expression (AACR-II 2020) - "Treatment with AXL TKI alone (RXDX-106 and R428) did not affect cell viability, but one EP clone demonstrated sensitivity to erlotinib when combined with R428 but not RXDX-106. Our data suggests that EPs have developed resistance through a combination of T790M and EMT-like state, with AXL upregulation as a common theme. One clone, harboring some T790M and osimertinib sensitivity, was also sensitive to erlotinib when combined with R428."

Oncology • AXL • BRAF • EGFR • KRAS • VIM • ZEB1

Immuno-oncological efficacy of RXDX-106, a novel TAM (TYRO3, AXL, MER) family small molecule kinase inhibitor (SITC 2017) - "RXDX-106 has the potential to restore and enhance immune function in macrophages and T cells, resulting in repolarization of the immune response towards an anti-tumor microenvironment. The unique mechanism of activating both innate and adaptive immunity, plus regulating cross-talk between immune cells and tumor cells by RXDX-106 supports clinical development of RXDX-106 to potentially treat a wide variety of cancers."

Checkpoint inhibition • Combination therapy • Oncology

Immuno-Oncological Efficacy of RXDX-106, a Novel Small Molecule Inhibitor of the TAM (TYRO3, AXL, MER) Family of Kinases. (PubMed, Cancer Res) - "RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced anti-tumor 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."

Clinical • IO Biomarker • Journal

Proteomic characterization of AXL kinase inhibitors and signaling pathways (AACR 2019) - "...AXL TKIs, RXDX106, R428 and Cabozantinib, were profiled using western blotting (WB), viability assay and activity-based protein profiling (ABPP)...We also show that AXL TKI fails to suppress downstream signaling, cell viability or EMT in EGFR TKI resistant cell lines. We have also established a PLA to annotate AXL adaptor foci that could be developed as a tool to measure drug-targetable active AXL complexes in patient tissues."