A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers

Roohullah, Aflah; Cooper, Adam; Lomax, Anna J; Aung, Jennifer; Barge, Alan; Chow, Lilian; McHale, Mark; Desai, Jayesh; Whittle, James R.; Souza, Paul de; Horvath, Lisa G.

doi:10.1007/s10637-018-0588-7

Cited by 18 publications

(7 citation statements)

References 28 publications

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“…We hypothesise that this approach may help overcome limitations of IGF-1R inhibitors used in the clinic such as on-target off-tumour induced hyperglycaemia since there is no appreciable RON expression in pancreatic epithelial cells, 56 there were no hyperglycaemic adverse events reported in an BMS-777607/ASLAN002 Phase 1 clinical trial. 57 In addition, we found that ET in combination with a RONi may prevent compensatory activation of the MAPK signalling pathway. GAB2 is a scaffolding protein that facilitates RTK pathway activation through interaction with PI3K subunits, and its overexpression in BC has been associated with PI3K and MAPK hyperactivity.…”

Section: Discussionmentioning

confidence: 69%

“…In a Phase 1 clinical trial (NCT01721148) evaluating the safety of the RON/MET inhibitor BMS-777607/ASLAN002 in solid cancers, BMS-777607/ASLAN002 was well-tolerated and five patients exhibited stable disease. 57 There are currently no Phase 2 trials evaluating the therapeutic efficacy of BMS-777607/ASLAN002, however, given our data we hypothesise that ESR1 -mutant expressing, RON-activated BCs may demonstrate sensitivity to vertical inhibition of the RON pathway using ET and a RONi. Our proteomic and immunoblot experiments demonstrated that ESR1 mutant-induced RON/PI3K activation was incompletely reduced with ET alone and that additional RON pathway blockade was required to achieve maximum therapeutic benefit.…”

Section: Discussionmentioning

confidence: 81%

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RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

Dustin

Beyer

et al. 2020

Br J Cancer

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Background Oestrogen Receptor 1 ( ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers. Methods We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d’Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model. Results We demonstrated that RON was hyperactivated in ESR1 mutant models, and in acquired palbociclib-resistant (PalbR) models. RON and insulin-like growth factor 1 receptor (IGF-1R) interacted as shown through pharmacological and genetic inhibition and were regulated by the mutant ER as demonstrated by reduced phospho-protein expression with endocrine therapies (ET). We show that ET in combination with a RON inhibitor (RONi) decreased ex vivo organoid growth of ESR1 mutant models, and as a monotherapy in PalbR models, demonstrating its therapeutic efficacy. Significantly, ET in combination with the RONi reduced metastasis of an ESR1 Y537S mutant PDX model. Conclusions Our results demonstrate that RON/PI3K pathway inhibition may be an effective treatment strategy in ESR1 mutant and PalbR MBC patients. Clinically our data predict that ET resistance mechanisms can also contribute to CDK4/6 inhibitor resistance.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 81%

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

Dustin

Beyer

et al. 2020

Br J Cancer

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“…Additionally, we hypothesize that disruption of RON/Axl signaling through the multi‐kinase inhibitor BMS777607 used herein can also sensitize patients with CRPC to ADT. BMS777607 has recently completed a Phase I clinical trial for advanced solid tumors, and our preclinical work illustrates a need to pursue the use of drugs such as this in prostate cancer patient studies 44 . Thus, BMS777607 and Axatilimab are exciting prospective agents for the treatment of CRPC.…”

Section: Discussionmentioning

confidence: 98%

Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6‐mediated Axl and RON signaling

et al. 2022

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Background: Androgen deprivation therapy (ADT), or chemical castration, is the first-line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor-associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration-resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell-intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON-overexpressing tumors alter macrophage function, we hypothesized that a macrophage-dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC.Methods: Using RON-modulated genetically engineered mouse models (GEMMs) and GEMM-derived cell lines and co-cultures with bone marrow-derived macrophages, we show functional and molecular characteristics of signaling pathways in supporting CRPC. Further, we used an unbiased phosphokinase array to identify pathway interactions regulated by RON. Finally, using human prostate cancer cell lines and prostate cancer patient data sets, we show the relevance of our findings to human prostate cancer. Results: Studies herein show that macrophages recruited into the prostate tumor microenvironment (TME) serve as a source for Gas6 secretion which serves to further enhance RON and Axl receptor activation in prostate tumor cells thereby driving CRPC. Further, we show targeting RON and macrophages in a murine model promotes CRPC sensitization to ADT. Conclusions: We discovered a novel role for the RON receptor in prostate cancer cells in promoting CRPC through the recruitment of macrophages into the prostate TME. Macrophage-targeting agents in combination with RON/Axl inhibition are likely to provide clinical benefits for patients with CRPC.

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“…BMS-777607 promoted antitumor, and antimetastatic activity, as well as host antitumor responses while synergizing with anti-PD-1 therapy. In a Phase I trial ( 220 ) (NCT01721148), the drug was considered well-tolerated. It resulted in long-term stable disease and partial responses in certain tumor types, leading to initiation of a Phase II trial and results pending (NCT00605618).…”

Section: Toward Standardization Of Axl-targeting Agents In Combinatio...mentioning

confidence: 99%

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

et al. 2022

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The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.

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A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers

Cited by 18 publications

References 28 publications

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6‐mediated Axl and RON signaling

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

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