Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

Kariolis, Mihalis S.; Miao, Yu; Diep, Anh Nguyet; Nash, Shannon E.; Olcina, Monica M.; Jiang, Dadi; Jones, D. S.; Kapur, Shiven; Mathews, I.I.; Koong, Albert C.; Rankin, Erinn B.; Cochran, Jennifer R.; Giaccia, Amato J.

doi:10.1172/jci85610

Cited by 94 publications

(90 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The AVB‐S6‐500 development program has been facilitated by a high sensitivity biomarker assay for serum GAS6. In preclinical oncology studies, abrogation of serum GAS6 correlated with effects on tumor metastasis, confirming serum GAS6 as a relevant serum biomarker to identify a pharmacologically active dose in humans. Model‐predicted GAS6 suppression aligned well with the observed data.…”

Section: Discussionmentioning

confidence: 77%

“…State‐of‐the‐art cancer treatments include antibodies and proteins designed to target specific dysregulated signaling pathways identified based on increasing knowledge of the molecular basis of cancer. Protein‐based therapeutics could provide many benefits, including a reduction in drug‐drug interactions with the background standard of care chemotherapeutic agents …”

mentioning

confidence: 99%

“…AXL, a member of the TAM family of receptor tyrosine kinases, is highly expressed in primary tumors and metastases in comparison with normal tissues and plays a role in tumor proliferation and survival, metastasis, and drug resistance . AXL has a single specific ligand, growth arrest‐specific 6 (GAS6) protein, which has also been implicated in poor prognosis, metastasis, and drug resistance in several forms of cancer . The expression of GAS6 is widespread in many tissues and cells, including immune cells, endothelial cells, vascular smooth muscle cells, bone marrow cells, adipocytes, platelets, and various cancer cells .…”

mentioning

confidence: 99%

“…Protein-based therapeutics could provide many benefits, including a reduction in drug-drug interactions with the background standard of care chemotherapeutic agents. [1][2][3] AXL, a member of the TAM family of receptor tyrosine kinases, is highly expressed in primary tumors and metastases in comparison with normal tissues and plays a role Serum GAS6 assay guides clinical dosing of AVB500 Bonifacio et al…”

mentioning

confidence: 99%

See 3 more Smart Citations

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

Bonifacio

Dodds²,

Prohaska

et al. 2019

Clinical Translational Sci

View full text Add to dashboard Cite

AVB‐S6‐500 neutralized growth arrest‐specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target‐mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first‐in‐human (FIH) doses for AVB‐S6‐500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB‐S6‐500 clearance was incorporated into a standard two‐compartment model, providing parallel linear and nonlinear clearance. Observed AVB‐S6‐500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10‐fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model‐projected and clinically observed maximal concentration (Cmax) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (Cmax) and 45% (area under the serum concentration‐time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB‐S6‐500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.

show abstract

Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

Bonifacio

Dodds²,

Prohaska

et al. 2019

Clinical Translational Sci

View full text Add to dashboard Cite

show abstract

“…In the case for the decoy receptors, elegant studies have engineered high affinity Axl decoy traps that bind and sequester Gas6 with femtomolar affinities52. These biologics show great promise as cancer therapeutics in aggressive pre-clinical models of human cancer with minimal overt toxicity, suggesting that targeting the Axl Ig1/Gas6 binding pocket is an attractive strategy for clinical developement.…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

Kimani

Kumar

Bansal

et al. 2017

Sci Rep

View full text Add to dashboard Cite

TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.

show abstract

GAS6‐expressing and self‐sustaining cancer cells in 3D spheroids activate the PDK‐RSK‐mTOR pathway for survival and drug resistance

2017

View full text Add to dashboard Cite

AXL receptor tyrosine kinase (RTK) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first‐line treatments. Furthermore, the AXL ligand growth arrest‐specific gene 6 (GAS6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL‐overexpressing tumor cell lines into non‐self‐sustaining and self‐sustaining subtypes in 3D spheroid culture. Self‐sustaining cells are characterized by excessive GAS6 secretion and TAM‐PDK‐RSK‐mTOR pathway activation. In 3D spheroid culture, the activation of the TAM‐PDK‐RSK‐mTOR pathway proves crucial following treatment with AXL/MET inhibitor BMS777607, when the self‐sustaining tumor cells react with TAM‐RSK hyperactivation and enhanced SRC‐AKT‐mTOR signaling. Thus, bidirectional activated mTOR leads to enhanced proliferation and counteracts the drug effect. mTOR activation is accompanied by an enhanced AXL expression and hyperphosphorylation following 24 h of treatment with BMS777607. Therefore, we elucidate a double role of AXL that can be assigned to RSK‐mTOR as well as SRC‐AKT‐mTOR pathway activation, specifically through AXL Y779 phosphorylation. This phosphosite fuels the resistance mechanism in 3D spheroids, alongside further SRC‐dependent EGFR Y1173 and/or MET Y1349 phosphorylation which is defined by the cell‐specific addiction. In conclusion, self‐sustenance in cancer cells is based on a signaling synergy, individually balanced between GAS6 TAM‐dependent PDK‐RSK‐mTOR survival pathway and the AXLY779/EGFR/MET‐driven SRC‐mTOR pathway.

show abstract

Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

Abstract: named as inventors. A.J. Giaccia and A.C. Koong are cofounders of Ruga Corp., a company that has licensed this patent.

Cited by 94 publications

References 45 publications

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

GAS6‐expressing and self‐sustaining cancer cells in 3D spheroids activate the PDK‐RSK‐mTOR pathway for survival and drug resistance

Contact Info

Product

Resources

About