AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells

Kim, Donghwa; Bach, Duc-Hiep; Fan, Yanhua; Luu, Thi-Thu-Trang; Hong, Ji‐Young; Park, Hyen Joo; Lee, Sang Kook

doi:10.1038/s41419-019-1601-6

Cited by 83 publications

(89 citation statements)

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“…Natural products have played an important role in the discovery of anticancer drugs (51). In our previous studies, we have found that yuanhuadine (YD), a daphnane-type diterpenoidal anti-tumor agent from the flowers of Daphne genkwa, can effectively suppress the growth of EGFR-TKIresistant NSCLC cells (21)(22)(23)52). Therefore, we further investigated whether the regulation of AGR2 can modulate EGFR-TKI resistance and whether resistance can be overcome by treating NSCLC cells with YD.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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Background/Aim: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. Materials and Methods: Using datasets from a pair of NSCLCsensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. Results: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. Conclusion: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide, and comprises 85% of all lung cancer cases (1). Acquired drug resistance in tumor cells is a major obstacle in the field of anti-cancer chemotherapies. Likewise, NSCLC patients who initially show a good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib (Gef), acquire resistance to treatment (2). However, studies on the mechanisms through which overexpression of specific genes is involved in EGFR-TKI resistanse of NSCLC cells are scarce and its role remains to be elucidated. Therefore, novel approaches are required to elucidate their role in drug resistanse of cancer cells. The anterior gradient-2 (AGR2) has been identified in Xenopus laevis and plays a critical role in cemet gland differentiation (3). Recent studies have suggested that elevated expression of AGR2 is correlated with cell proliferation, metastasis, and drug resistance in various human cancer cell lines, such as prostate (4), breast (5), and pancreatic cancer (6). Moreover, overexpression of AGR2 has been notably correlated with a poor outcome of estrogen receptor-negative breast cancer patients (7). AGR2 is also a pro-oncogenic protein that has been shown to stimulate the epidermal growth factor receptor (EGFR) ligand amphiregulin, regulate p53 signaling, and interact with the AAA+ protein Reptin (8), suggesting its modulatory roles in gene expression. High expression of AGR2 has also been shown to be predictive of poor survival in lung cancer (9). However, there is still a lack of insightful understanding of the role of AGR2 in EGFR-TKI-resistant NSCLC cells. There are 19 members of zinc-dependent metalloproteases in the family of a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) (10). Recent reports suggest the critical roles of ADAMTSs in angiogenesis and cancer (11). They also play an important role in the modulation of extracellular matrix. For instance, ADAMTS-1 metallopro...

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Section: Discussionmentioning

confidence: 99%

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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“…Osimertinib resistant can occur via oncogenic shift to alternative RTKs including c-MET (11), HER2 and/or HER3 (7-9), IGF1R (12), and AXL (13)(14)(15)(16). 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 Combining osimertinib with a MEK inhibitor can enhance osimertinib efficacy (10,17,20,56,57) and Phase II clinical trials are currently underway to assess combining osimertinib with the MEK inhibitor selumetinib in EGFR-mutated NSCLC (NCT03392246), although resistance to combined osimertinib and MEK inhibition still occurs (17).…”

Section: Discussionmentioning

confidence: 99%

“…The most common EGFR-independent resistance mechanisms involve reactivation of the RTK/RAS/effector pathway (10), often via enhanced signaling through parallel RTKs (7)(8)(9)(11)(12)(13)(14)(15)(16). 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.…”

Section: Introductionmentioning

confidence: 99%

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

Theard

Sheffels

Sealover

et al. 2020

Preprint

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Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR-and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.of RAS, co-targeting intermediates of the RAF/MEK/ERK and PI3K/AKT pathways enhances of osimertinib effectiveness, however, signaling through the uninhibited effector pathway may drive resistance (17)(18)(19)(20). Thus, it may be important for therapeutic combinations including osimertinib to stifle all downstream RTK/RAS signaling to be effective.Recent studies suggest that pharmacologic assessments of targeted therapeutics should be performed under 3D culture conditions rather than in 2D adherent cultures (21,22). 3D spheroids show altered growth characteristics, changes in cell surface proteins, altered metabolism, changes in activation of signaling pathways or altered responses to targeted pathway inhibitors, and are more resistant to drug-induced apoptosis compared to 2D adherent cultures signaling (23-26). These differences may be particularly relevant in EGFR-mutated NSCLC. EGFR-mutated cells show differential RTK expression and phosphorylation in 3D versus 2Dconditions (27). Further, EGFR-mutated cells respond more robustly to first-generation EGFR-TKIs in 3D cultures, and these responses more closely resemble responses seen in vivo (28).These data highlight the need for pharmacologic assessment of therapeutics designed to treat EGFR-mutated NSCLC under 3D culture conditions. The ubiquitously expressed RasGEFs (guanine nucleotide exchange factors) SOS1 and SOS2 (son of sevenless 1 and 2) are common signaling intermediates of RTK-mediated RAS activation. Although not initially considered as drug targets because of the low oncogenic potential of SOS (29), there has been renewed interest in SOS proteins as therapeutic targets for cancer treatment. We and others have shown that SOS1 and SOS2 may be important therapeutic targets in KRAS-mutated cancer cells (30-32), and a specific SOS1 inhibitor (BAY-293) has recently been identified (33). Here, we investigate SOS1 and SOS2 as potential therapeutic targets in EGFR-mutated l...

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“…Treatment of NSCLC lines with an AXL inhibitor in combination with erlotinib restored sensitivity to erlotinib [80]. AXL is also able to mediate resistance to a newer EGFR-targeted inhibitor, osimertinib, in NSCLC [81][82][83]. is resistance is thought to be mediated by AXL interacting with EGFR and HER3 [82].…”

Section: Targeted Erapiesmentioning

confidence: 99%

AXL as a Target in Breast Cancer Therapy

Colavito

2020

Journal of Oncology

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AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, and a role for AXL in modulation of the tumor microenvironment and immune response has been identified. In light of these activities multiple AXL inhibitors have been developed, and several of these have entered clinical trials in the U.S. In breast cancer, high levels of AXL expression have been observed. The role of AXL in cancer with a focus on therapeutic implications for breast cancer is discussed.

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AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells

Cited by 83 publications

References 50 publications

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

AXL as a Target in Breast Cancer Therapy

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