AXL/MET dual inhibitor, CB469, has activity in non-small cell lung cancer with acquired resistance to EGFR TKI with AXL or MET activation

Yang, Yao; Jang, Yoon; Lee, Sang Hyuk; Kang, Beodeul; Lim, Sun Min

doi:10.1016/j.lungcan.2020.05.031

Cited by 13 publications

(17 citation statements)

References 24 publications

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“… 42 For instance, a confluence of preclinical and translational data suggests that EGFR mutant patients receiving EGFR TKI may benefit from a combination with an AXL inhibitor. 73 , 74 …”

Section: Strategies To Overcome Axl Mediated Therapy Resistancementioning

confidence: 99%

Targeting AXL in NSCLC

Zaman

Bivona

2021

LCTT

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State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL’s role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL’s role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.

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“… 42 For instance, a confluence of preclinical and translational data suggests that EGFR mutant patients receiving EGFR TKI may benefit from a combination with an AXL inhibitor. 73 , 74 …”

Section: Strategies To Overcome Axl Mediated Therapy Resistancementioning

confidence: 99%

Targeting AXL in NSCLC

Zaman

Bivona

2021

LCTT

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“…We classified the AR mechanisms into five categories: (a) aberration of EGFR itself, (b) activation of bypass signaling, (c) suppression of apoptosis, (d) EMT, and (e) other mechanisms. Mechanisms of acquired resistance to first-line osimertinib that were identified in cell line models [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]48,[50][51][52][53][54][55][56][57][58][59][60]. This graph is color-coded by cell line models and mechanisms of resistance to first-line osimertinib.…”

Section: Search Criteria For Published Studiesmentioning

confidence: 99%

“…Molecules and pathways that may have roles in AR to first-line osimertinib are summarized in Figure 2. Scheme of the signal pathway and molecules that reportedly cause osimertinib resistance-AXL [39,41,52], HER3 [45], IGF1R [51,57], MET [33,52], TGFβ1 [40], TGFβ2 [59], BRAF [43], RAS [32,35], ERK [37], Src-AKT [35], ACK1 [48], CDK4/6 [55], BCL-2 [56], MCL-1 [34], BIM [34,50], YAP [54], ANKRD1 [36], microRNA-200c [46], ZEB1 [46,58], and IRE1α [38] (highlighted in red)-in cell line models treated with osimertinib. EGFR, epidermal growth factor receptor; AXL, AXL receptor tyrosine kinase; ERBB3, human epidermal growth factor receptor-3; IGF1R, insulin-like growth factor-1 receptor; MET, MET proto-oncogene, receptor tyrosine kinase; TGF, transforming growth factor; ACK1, activated Cdc42associated kinase-1; CDK4/6, cyclin-dependent kinase; BCL-2, B-cell lymphoma-2; YAP, yes-associated protein; ANKRD1, ankyrin repeat domain-1; IRE1α, inositol-requiring enzyme-1α.…”

Section: Activation Of Bypass Signalingmentioning

confidence: 99%

“…Originally, AR mediated by AXL was reported in HCC827 cells that acquired resistance to the first-generation EGFR-TKI, erlotinib [65]. As a resistance mechanism against first-line osimertinib, cells that acquired resistance through the activation of AXL and MET were established from HCC827 cells; a combination of an AXL/MET dual inhibitor (CB469) plus osimertinib could overcome the resistance [52]. Additionally, another group reported establishing acquired resistant PC9, H1975, and HCC4006 cell lines with AXL activation.…”

Section: Axl Activationmentioning

confidence: 99%

“…In the 27 remaining studies, 17 AR cell lines were established from PC9 cells, 16 from H1975 cells (L858R plus T790M, a cell line model with primary resistance to first-or second-generation EGFR-TKIs), 10 from HCC827 cells, and 2 from HCC4006 cells ( Figure 1). Twenty-five studies used chronic exposure to osimertinib at increasing concentrations, one study [57] used chronic exposure to osimertinib at a consistent concentration, and one study [52] used two different exposures (increasing concentration and a consistent concentration). We classified the AR mechanisms into five categories: (a) aberration of EGFR itself, (b) activation of bypass signaling, (c) suppression of apoptosis, (d) EMT, and (e) other mechanisms.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

Ohara

Suda

Mitsudomi

2021

Cells

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial–mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.

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Advances and challenges in the treatment of lung cancer

Li,

Yan,

2023

Biomedicine & Pharmacotherapy

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AXL/MET dual inhibitor, CB469, has activity in non-small cell lung cancer with acquired resistance to EGFR TKI with AXL or MET activation

Cited by 13 publications

References 24 publications

Targeting AXL in NSCLC

Targeting AXL in NSCLC

Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

Advances and challenges in the treatment of lung cancer

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