DS-1205b, a novel selective inhibitor of AXL kinase, blocks resistance to EGFR-tyrosine kinase inhibitors in a non-small cell lung cancer xenograft model

Abstract

The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration in vitro and exerted significant antitumor activity in vivo . AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.

AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells

“…This was recently and independently confirmed using a different AXL kinase inhibitor (DS-1205), in which combinational treatment with DS-1205 and the third-generation EGFR inhibitor osimertinib significantly delayed the onset of resistance compared with osimertinib treatment alone in an HCC827 xenograft model. 59 This is consistent with a recent study showing that acquired resistance to BRAFi in melanoma cells in vitro is derived from transient AXL-expressing drug-resistant (AXL jackpot) cells. 10 In addition, in NSCLC, a recent report suggests AXL as an important contributor to overcome the initial drug response against osimertinib.…”

Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer

“…Osimertinib resistant can occur via oncogenic shift to alternative RTKs including c-MET ( Shi et al, 2016 ), HER2 and/or HER3 ( Mancini et al, 2018 ; Romaniello et al, 2018 ; La Monica et al, 2017 ), IGF1R ( Park et al, 2016 ), and AXL ( Kim et al, 2019 ; Taniguchi et al, 2019 ; Jimbo et al, 2019 ; Namba et al, 2019 ). The variety of RTK bypass pathways that can lead to osimertinib resistance suggests that broad inhibition of RTK signaling may be a more effective therapeutic strategy than any individual RTK inhibitor to limit osimertinib resistance, whereas once resistance via oncogenic shift to an alternative RTK occurs then inhibition of the upregulated RTK would have therapeutic benefit.…”

“…Unlike first-generation EGFR-TKIs, mechanisms driving osimertinib resistance are more variable, including both EGFR-dependent (10–30%) and EGFR-independent mechanisms ( Mancini et al, 2018 ; Romaniello et al, 2018 ; La Monica et al, 2017 ; Eberlein et al, 2015 ). The most common EGFR-independent resistance mechanisms involve reactivation of the RTK/RAS/effector pathway ( Eberlein et al, 2015 ), often via enhanced signaling through parallel RTKs ( Mancini et al, 2018 ; Romaniello et al, 2018 ; La Monica et al, 2017 ; Shi et al, 2016 ; Park et al, 2016 ; Kim et al, 2019 ; Taniguchi et al, 2019 ; Jimbo et al, 2019 ; Namba et al, 2019 ). Here, combining osimertinib with individual RTK inhibitors can both inhibit the development of resistance through the inhibited RTK and kill cancer cells with resistance driven by the specific RTK being inhibited.…”

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

“…Forced expression of an active form of AXL, but not a kinase-impaired AXL, in erlotinib-sensitive tumor cells was sufficient to induce erlotinib resistance [ 53 ]. AXL or GAS6 knockdown [ 53 ], AXL degradation [ 75 , 198 ], treatment with an AXL blocking antibody [ 70 ], or treatment with the small molecule AXL inhibitors XL-880 [ 53 ], MP-470 [ 53 ], SGI-7079 [ 112 ], MGCD265 [ 199 ], MGCD516 [ 199 ], DS-1205b [ 200 ], or R428 [ 199 , 201 ] sensitized NSCLC cells to first generation EGFR TKIs (gefitinib or erlotinib) and delayed onset of resistance relative to EGFR TKI alone [ 200 ]. Similarly, MERTK overexpression was sufficient to confer erlotinib resistance in a mt EGFR -expressing NSCLC cell line and treatment with a MERTK-selective inhibitor re-sensitized the cells to erlotinib [ 55 ].…”