dubermatinib (TP-0903)

Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.

Finally, we demonstrated that TP-0903 significantly diminished the tumor growth and DKK1 expression in xenograft mice. Collectively, our findings indicate that TP-0903 triggers apoptotic cell death of NB cells, attributing to the ROS-mediated miR-335-3p upregulation and the consequent DKK1 downregulation.

These findings suggest the activation of an atypical ferroptosis pathway mediated through the TGF-β1/SMAD3 signaling pathway. Overall, these data indicate that TP-0903 may offer a novel therapeutic strategy for the treatment of refractory hematological malignancies.

To this end, this study aims to evaluate the antitumor efficacy of a combined treatment with low doses of different molecular targeted drugs, i.e. Y15, a FAK inhibitor, Afatinib (AFA) an ErbB inhibitor and TP-0903, an Axl inhibitor, on HNC. Moreover, as compared to the individual inhibitors and their pairwise combinations, the triple drug combination was the only able to simultaneously downregulate Axl, FAK, and N-cadherin while upregulating E-cadherin expression levels. The results reported herein provide compelling preliminary evidence supporting the combined use of Y15, AFA and TP-0903 as a novel therapeutic strategy for HNCs.

The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.

AXL signaling promotes IBC growth by inducing M2 macrophage polarization and driving the secretion of immunosuppressive molecules and cytokines via STAT6 signaling, thereby contributing to an immunosuppressive TME. Collectively, these findings highlight the potential of targeting AXL signaling as a novel therapeutic approach for IBC that warrants further investigation in clinical trials.

Moreover, in addition to tumor suppression, the combination therapy of TP-0903 and WIN55212-2 induced the infiltration of cytotoxic CD8+ T cells and significantly reduced mTOR and STAT3 activation in tumor tissues of C57BL/6J mice bearing MC-38 cells. This study demonstrated that targeting AXL could sensitize cannabinoids to cancer therapy by interfering with tumor cells and tumor-infiltrating CD8+ T cells.

In summary, our study elucidated the effects of DSP-0509 on immune activity within the tumor microenvironment. These findings provided valuable insights that pave the way for the development of novel combination immunotherapy strategies.

Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment.

P1, N=177, Completed, Sumitomo Pharma America, Inc. | Phase classification: P1a --> P1

We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.