Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

Bhalla, Sheena; Fattah, Farjana J.; Ahn, Chul; Williams, Jessica N.; Macchiaroli, Alyssa; Padro, Jonathan; Pogue, Meredith; Dowell, Jonathan E.; Putnam, William C.; McCracken, Nigel W.; Micklem, David; Brekken, Rolf A.; Gerber, David E.

doi:10.1016/j.lungcan.2023.107291

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…Although there are promising clinical trials and studies targeting AXL [ 67 , 68 ], redundancy of signaling through other TAM (TYRO3, AXL, and MERTK) family kinases may decrease their effectiveness [ 69 ]. These phenomena invoke the combination of anti-EGFR/HER treatments with TAM inhibitors to replace monotherapy [ 70 , 71 , 72 , 73 , 74 , 75 ] as well as the development of pan-TAM inhibitors [ 76 , 77 ]. Clinical resistance to AXL-targeting therapies may also involve HER3 [ 78 ], but this requires further investigation [ 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Ujlaky-Nagy,

Szöllősi,

Vereb

2024

IJMS

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Pertuzumab (Perjeta®), a humanized antibody binding to the dimerization arm of HER2 (Human epidermal growth factor receptor-2), has failed as a monotherapy agent in HER2 overexpressing malignancies. Since the molecular interaction of HER2 with ligand-bound EGFR (epidermal growth factor receptor) has been implied in mitogenic signaling and malignant proliferation, we hypothesized that this interaction, rather than HER2 expression and oligomerization alone, could be a potential molecular target and predictor of the efficacy of pertuzumab treatment. Therefore, we investigated static and dynamic interactions between HER2 and EGFR molecules upon EGF stimulus in the presence and absence of pertuzumab in HER2+ EGFR+ SK-BR-3 breast tumor cells using Förster resonance energy transfer (FRET) microscopy and fluorescence correlation and cross-correlation spectroscopy (FCS/FCCS). The consequential activation of signaling and changes in cell proliferation were measured by Western blotting and MTT assay. The autocorrelation functions of HER2 diffusion were best fitted by a three-component model corrected for triplet formation, and among these components the slowly diffusing membrane component revealed aggregation induced by EGFR ligand binding, as evidenced by photon-counting histograms and co-diffusing fractions. This aggregation has efficiently been prevented by pertuzumab treatment, which also inhibited the post-stimulus interaction of EGFR and HER2, as monitored by changes in FRET efficiency. Overall, the data demonstrated that pertuzumab, by hindering post-stimulus interaction between EGFR and HER2, inhibits EGFR-evoked HER2 aggregation and phosphorylation and leads to a dose-dependent decrease in cell proliferation, particularly when higher amounts of EGF are present. Consequently, we propose that EGFR expression on HER2-positive tumors could be taken into consideration as a potential biomarker when predicting the outcome of pertuzumab treatment.

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Section: Discussionmentioning

confidence: 99%

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Ujlaky-Nagy,

Szöllősi,

Vereb

2024

IJMS

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“…The AXL inhibitor R428 (also called BGB324 or Bemcentinib), which is very selective for AXL among TAMs and other receptor tyrosine kinases, is the subject of several active clinical trials [23]. The administration of Bemcentinib was linked to changes in proteins involved in the metabolism of reactive oxygen species, protein kinase B signaling, and other processes, indicating a significant anti-tumor effect in patients with non-small cell lung cancer [24]. Growth arrest-specific gene 6 (Gas6) is a cytokine that binds to Tyro3, AXL, and Mer receptor tyrosine kinases [25].…”

Section: Of 17mentioning

confidence: 99%

Signaling Pathways of AXL Receptor Tyrosine Kinase Contribute to the Pathogenetic Mechanisms of Glioblastoma

Repici,

Ardizzone,

De Luca

et al. 2024

Cells

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Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most common and most aggressive form of the primary brain tumors. Indeed, despite the best treatments available including surgery, radiotherapy or a pharmacological approach with Temozolomide, glioblastoma patients’ mortality is still high, within a few months of diagnosis. Therefore, to increase the chances of these patients surviving, it is critical to keep finding novel treatment opportunities. In the past, efforts to treat glioblastoma have mostly concentrated on customized treatment plans that target specific mutations such as epidermal growth factor receptor (EGFR) mutations, Neurotrophic Tyrosine Receptor Kinase (NTRK) fusions, or multiple receptors using multi-kinase inhibitors like Sunitinib and Regorafenib, with varying degrees of success. Here, we focused on the receptor tyrosine kinase AXL that has been identified as a mediator for tumor progression and therapy resistance in various cancer types, including squamous cell tumors, small cell lung cancer, and breast cancer. Activated AXL leads to a significant increase in tumor proliferation, tumor cell migration, and angiogenesis in different in vitro and in vivo models of cancer since this receptor regulates interplay with apoptotic, angiogenic and inflammatory pathways. Based on these premises, in this review we mainly focused on the role of AXL in the course of glioblastoma, considering its primary biological mechanisms and as a possible target for the application of the most recent treatments.

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“…Independently in oncology, AXL has also been shown to have a prominent role in cell differentiation and proliferation in cancer cells. Therefore, a small molecule inhibitor of AXL, bemcentinib, which selectively binds to the intracellular catalytic kinase domain of AXL, is a licensed therapy currently in multiple Phase II trials for the treatment of breast, lung, and myeloid neoplasms ( 10 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

Jordan,

Tunbridge,

Husain

et al. 2024

JCI Insight

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Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

Cited by 6 publications

References 28 publications

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Disrupting EGFR–HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome

Signaling Pathways of AXL Receptor Tyrosine Kinase Contribute to the Pathogenetic Mechanisms of Glioblastoma

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

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