- |||||||||| Journal: Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors. (Pubmed Central) - Apr 12, 2024
Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.
- |||||||||| cisplatin / Generic mfg.
Journal: In Situ Nanofiber Formation Blocks AXL and GAS6 Binding to Suppress Ovarian Cancer Development. (Pubmed Central) - Mar 28, 2024
Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors...Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. We anticipate that our Nap-IR can be applied in clinical ovarian cancer therapy in the near future.
- |||||||||| Journal, Tumor cell: AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells. (Pubmed Central) - Mar 26, 2024
In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.
- |||||||||| Leclaza (lazertinib) / J&J
Targeting AXL and MCL-1 to eradicate lazertinib tolerance in EGFR-mutated NSCLC cells (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_9297;
Cell-based assays showed that triple therapy with an MCL-1 or YAP inhibitor, in combination with EGFR-TKI lazertinib, an AXL inhibitor, significantly reduced cell viability and increased apoptosis. These results demonstrate that AXL and YAP/MCL-1 signals contribute to the adaptive lazertinib resistance in EGFR-mutant NSCLC cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be highly effective in eliminating lazertinib-resistant cells.
- |||||||||| c-Met/AXL crosstalk in mediating therapeutic resistance in renal cell carcinoma (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_6711;
We have also found that prolonged treatment of c-Met inhibitor Cabo, (including Crizotinib and PF-4217903) induced c-Met and AXL overexpression in RCC cells...Furthermore, either silencing of AXL (using siRNA) or inhibiting AXL (using TP0903) induced significant apoptosis in these Cabo-resistant cells. Together, our data suggest that inhibition of AXL along with c-Met can be beneficial in preventing acquired therapeutic resistance in RCC.
- |||||||||| ABT-101 / Anbogen Therap
Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs (Section 20) - Mar 5, 2024 - Abstract #AACR2024AACR_3588;
BPR5K230 effectively addressed sorafenib resistance in the Hepa 1-6 model and exhibited significant synergistic antitumor effects when combined with an anti-PD-L1 antibody in the EMT-6 model. As a result, BPR5K230 represents a promising dual AXL/MER kinase inhibitor, and further preclinical evaluation is underway for its development as a potential anticancer and immune-modulating drug.
- |||||||||| DUSP4 Suppresses Lymph Node Metastasis In Cervical Cancer By Mediating AXL Degradation (Poster area) - Jan 18, 2024 - Abstract #ESGO2024ESGO_800;
DUSP4 induces ubiquitination and proteasomal degradation of AXL via TRIM21, which is a noted E3 ubiquitin-protein ligase. Finally, the efficacy of AXL inhibitor in hindering LNM were validated in vivo.Conclusion These data suggest that cross-talk of DUSP4 and AXL plays an important role in regulation of cervical cancer LNM, and AXL inhibitor successfully impedes the process, which further contributes to treatment of advanced cervical cancer.
- |||||||||| Journal: Gas6-Axl Signaling Induces SRF/MRTF-A Gene Transcription via MICAL2. (Pubmed Central) - Dec 27, 2023
The physiological significance of the Gas6/Axl-MICAL2 signaling pathway described here is supported by the marked gene expression correlation across a broad array of different cancers between MICAL2 and Axl and Gas6, as well as the coexpression of these genes and the known SRF/MRTF-A target transcripts. Overall, these data reveal a new link between Gas6/Axl and SRF/MRTF-A-dependent gene transcription and link MICAL2 as a novel effector of the Gas6/Axl signaling pathway.
- |||||||||| Journal: Rational Combinations of PARP Inhibitors with HRD-Inducing Molecularly Targeted Agents. (Pubmed Central) - Nov 22, 2023
Cancers with wild-type BRCA, homologous recombination proficiency, or de novo or acquired resistance to PARP inhibition represent a growing population of patients who may benefit from combinatorial PARP inhibitor strategies. We review targeted inhibitors of angiogenesis, epigenetic regulators, and PI3K, MAPK, and other cellular signaling pathways as inducers of homologous recombination deficiency, providing support for the use of PARP inhibitors in contexts not previously considered susceptible to PARP inhibition.
- |||||||||| dubermatinib (TP-0903) / Sumitomo Pharma
Phase classification, Metastases: First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - Nov 14, 2023
P1, N=177, Completed,
We review targeted inhibitors of angiogenesis, epigenetic regulators, and PI3K, MAPK, and other cellular signaling pathways as inducers of homologous recombination deficiency, providing support for the use of PARP inhibitors in contexts not previously considered susceptible to PARP inhibition. Phase classification: P1a --> P1
- |||||||||| SHP099 / Novartis, Xospata (gilteritinib) / Astellas
SHP2 Inhibition Overcomes Adaptive and Acquired Resistance to FLT3 TKI to Improve Efficacy Against FLT3/ITD AML (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_3737;
The addition of SHP099 to sorafenib decreased the expected ERK reactivation in a dose-dependent manner...The combination of SHP099 with gilteritinib group resulted in a statistically significantly lower leukemia burden compared to either treatment alone and the vehicle control...While daunorubicin or cytarabine alone had little effect on the level of phosphorylated ERK, the addition of SHP099 decreased ERK activation and the combination synergized to exert greater to decrease proliferation and increase apoptosis...The finding that SHP099 synergized with both FLT3 TKI and chemotherapy agents in different FLT3-mutated AML models speaks to the versatile efficacy of SHP2 inhibition in multiple AML models. Taken together, the data suggests that SHP2 inhibition can help overcome both adaptive and acquired resistance in FLT3/ITD AML and is a candidate to try to improve patient outcomes.
- |||||||||| Review, Journal: AXL - a new player in resistance to HER2 blockade. (Pubmed Central) - Oct 21, 2023
Furthermore, AXL shows a strong value as a prognostic and predictive biomarker in HER2+ breast cancer patients, adding a remarkable translational relevance. Therefore, current studies enforce the potential of co-targeting AXL and HER2 to overcome resistance and supports the use of AXL inhibitors in the clinic.
- |||||||||| Bavencio (avelumab) / EMD Serono, batiraxcept (AVB-500) / Aravive
Trial primary completion date, Combination therapy, Metastases: COAXIN: Avelumab in Combination With AVB-S6-500 in Patients With Advanced Urothelial Carcinoma (clinicaltrials.gov) - Oct 13, 2023
P1, N=19, Active, not recruiting,
Therefore, current studies enforce the potential of co-targeting AXL and HER2 to overcome resistance and supports the use of AXL inhibitors in the clinic. Trial primary completion date: Aug 2023 --> Jan 2024
- |||||||||| ceralasertib (AZD6738) / AstraZeneca
Effect of combinational targeted therapy for AXL and ATR against malignant mesothelioma cells (Exhibition area) - Oct 6, 2023 - Abstract #ESMOAsia2023ESMO_Asia_1025;
As for the systemic treatment, combination therapy with the cytotoxic anticancer drugs, cisplatin and pemetrexed, have been used to treat inoperable MM...Methods To evaluate the impact of ataxia telangiectasia and Rad3-related protein (ATR) inhibition in MM cells, we examined the efficacy of the ATR inhibitor AZD6738 on cell growth inhibition using 14 MM cell lines...CDX models showed that this novel combination significantly attenuated tumor growth compared with each monotherapy. Conclusions Our observations showed that optimal AXL and ATR inhibition may potentially improve the outcome of patients with MM.
- |||||||||| AXL-targeted macrophage phenotype switching mediates checkpoint-resistance in melanoma (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_1294;
Analysis is ongoing to define spatial intratumoral, intranodal, and geographic intertumoral heterogeneity. Our data provide mechanistic insight to the potential for macrophage-specific and AXL-directed therapy to improve immunotherapeutic response and further exploration of potential as a predictive biomarker is warranted.
- |||||||||| AB801 / Arcus Biosci
Inhibition of AXL signaling with AB801 augments anti-tumor immune responses (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_1205;
Conclusions AXL is a promising therapeutic target involving both immunomodulatory and tumor-intrinsic mechanisms. The potent and selective AXL inhibitor AB801 reduces immunosuppression in the TME, enables activation of an anti-tumor immune responses, and renders tumors more susceptible to checkpoint blockade and chemotherapeutic treatment.
- |||||||||| TNG260 / Tango Therap
CoREST inhibition by TNG260 increases expression of immunomodulatory genes in STK11-mutant cancer and sensitizes to immune checkpoint blockade (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_1197;
Background Loss of function mutations in STK11 drive immune evasion and cause resistance to immune checkpoint blockade...Similarly, the AXL inhibitor, bemcentinib, provided a minor enhancement to the tumor growth inhibition seen with anti-PD1 as a single agent in this model...Unlike other small molecules being combined with anti-PD1 for STK11-deficient NSCLC, the combination of TNG260 with anti-PD1 drives tumor regressions in STK11-deficient models that are typically resistant to anti-PD1 monotherapy. TNG260 is under investigation in a Phase 1/2 study as a single agent and in combination with pembrolizumab for patients with STK11-mutated, advanced solid tumors.
- |||||||||| bemcentinib (BGB324) / BerGenBio
Journal: Targeting CD301 macrophages inhibits endometrial fibrosis and improves pregnancy outcome. (Pubmed Central) - Sep 12, 2023
Mechanistically, CD301 macrophages secreted GAS6 to activate the AXL/NF-?B pathway, upregulating the profibrotic protein synthesis. Targeted deletion of CD301 macrophages or inhibition of AXL by Bemcentinib blunted the pathology and improved the outcomes of pregnancy in mice, supporting the therapeutic potential of targeting CD301 macrophages for treating endometrial fibrosis.
- |||||||||| pexmetinib (ARRY-614) / Pfizer
Journal: In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL. (Pubmed Central) - Sep 11, 2023
Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis...Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFR mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma.
- |||||||||| Journal, CAR T-Cell Therapy: AXL inhibition improves the anti-tumor activity of chimeric antigen receptor T cells. (Pubmed Central) - Sep 4, 2023
AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CART cells, Th2 cytokines, reversal of CART-cell inhibition, and promotion of CART-cell effector functions. AXL inhibition is a novel strategy to enhance CART-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CART-cell inhibition through selective targeting of M2-polarized macrophages.
- |||||||||| bemcentinib (BGB324) / BerGenBio
Journal: Triple?negative breast cancer cells that survive ionizing radiation exhibit an Axl?dependent aggressive radioresistant phenotype. (Pubmed Central) - Aug 24, 2023
Combined radiotherapy with Axl inhibition by treatment with R428 and small interfering RNA lentivirus targeting Axl infection significantly reduced cell viability, colony formation ability, DNA double-stranded break repair, and the invasive and migratory ability of 4T-1/IRR cells...The results of western blotting showed that the critical molecular mechanism involved in the radioresistance of TNBC cells was the PI3K/Akt/mTOR signaling pathway induced by Axl activation. Thus, it is hypothesized that targeted Axl therapy combined with radiotherapy may have significant potential for the treatment of TNBC.
- |||||||||| Xospata (gilteritinib) / Astellas, MRX2843 / Meryx, RXDX-106 / Roche
Journal: Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction. (Pubmed Central) - Aug 22, 2023
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.
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