Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in<i>EGFR</i>-Mutant Non–Small Cell Lung Cancer Cells

Namba, Kei; Shien, Kazuhiko; Takahashi, Yuta; Torigoe, Hidejiro; Sato, Hiroki; Yoshioka, Takahiro; Takeda, Tatsuaki; Kurihara, Eisuke; Ogoshi, Yusuke; Yamamoto, Hiromasa; Soh, Junichi; Tomida, Shuta; Toyooka, Shinichi

doi:10.1158/1541-7786.mcr-18-0628

Cited by 77 publications

(89 citation statements)

References 47 publications

(46 reference statements)

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“…The percentage of AXL‐positive patients was thus 25% (3/12) before EGFR‐TKI treatment and 47% (9/19) after treatment failure, consistent with the previous finding that ~20% of patients showed upregulation of AXL after the development of EGFR‐TKI resistance . Given that AXL has also been shown to confer de novo resistance to EGFR‐TKIs, and a recent preclinical study has shown that AXL expression was increased after resistance to Osimertinib in EGFR mutant cells, the combination of an EGFR‐TKI and an AXL inhibitor may be warranted for EGFR‐TKI–naïve patients and patients with acquired resistance to EGFR‐TKIs.…”

Section: Discussionsupporting

confidence: 86%

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

et al. 2019

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Background Non‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR‐tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one‐fifth of NSCLC patients with acquired resistance to EGFR‐TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. Methods Tumor tissue and plasma specimens were collected from 25 EGFR‐mutated NSCLC patients before EGFR‐TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme‐linked immunosorbent assays. Results AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR‐TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. Conclusion Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR‐mutated NSCLC.

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Section: Discussionsupporting

confidence: 86%

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

et al. 2019

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“…In contrast, expression of E-cadherin and vimentin was similar in PC9 and PC9-ER cells Figure 2D), with PC9-ER cells having a lower invasion potential than their parental counterparts (0.52 relative invading fraction in PC9-ER compared to PC9 parental cells; Figure 2E). Similar results were previously reported by others: PC9 cells with acquired resistance to osimertinib maintained epithelial phenotype, while H1975 osimertinib-resistant cells developed mesenchymal features [28][29][30]. Overall, two out of three EGFR TKI-resistant models we developed (H1975-OR and SH416-ER) underwent EMT.…”

Section: Egfr Tki Resistance Is Associated With Emtsupporting

confidence: 90%

“…This is an important discovery since it points towards a potential opportunity to utilize vitamin D-based combination therapies in the setting of progressive disease. As a mechanism of resistance to EGFR TKIs, EMT is commonly observed in pre-clinical models [7,[27][28][29][30]44]. In the clinic, EMT is believed to cause EGFR TKI failure in a small proportion (~6%) of EGFR-mutant LUAD patients [4].…”

Section: 25(oh)2d3 Is Known To Induce Transcription Of Multiple Celmentioning

confidence: 99%

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Shaurova

Battaglia

et al. 2020

Cancers

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EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vitamin D metabolites could be used with EGFR TKIs to prevent therapeutic failure. To test this idea, we investigated the link between serum 25-hydroxyvitamin D3 (25(OH)D3) and progression-free survival (PFS) in patients with EGFR-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patients who were 25(OH)D3-sufficient experienced significantly longer benefit from EGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, p = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with KRAS-mutant LUAD that received cytotoxic chemotherapy. To gain mechanistic insights, we tested 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity in vitro. 1,25(OH)2D3 promoted epithelial differentiation and restored EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial-mesenchymal transition (EMT). 1,25(OH)2D3 was ineffective in a non-EMT model of resistance. We conclude that vitamin D sufficiency portends increased PFS among EGFR-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT.

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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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Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment inEGFR-Mutant Non–Small Cell Lung Cancer Cells

Cited by 77 publications

References 47 publications

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

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

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