Abstract A49: Acquired resistance of non-small cell lung cancer to EGFR-TKI: Role of AKT3

Epithelial to mesenchymal transition (EMT) is associated with resistance during EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Here, we investigated whether EMT is associated with acquired resistance to 3rd generation EGFR-TKIs, and we explored the effects of cyclin-dependent kinase 7 (CDK7) inhibitors on EMT-mediated EGFR-TKIs resistance in non-small cell lung cancer (NSCLC). We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. The two resistant cell lines showed phenotypic changes to a spindle-cell shape, had a reduction of epithelial marker proteins, an induction of vimentin expression, and enhanced cellular mobility. The EMT-related resistant cells had higher sensitivity to THZ1 than the parental cells, although THZ1 treatment did not inhibit EGFR activity. This phenomenon was also observed in TGF-β1 induced EMT cell lines. THZ1 treatment induced G2/M cell cycle arrest and apoptosis in all of the cell lines. In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.

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EGFR-TKI rechallenged treatment combined with apatinib in non-small cell lung cancer with EGFR-TKI resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20529 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20529-e20529 ◽

Cited By ~ 1

Author(s):

Li Liang ◽

Fang Li ◽

Baoshan Cao ◽

Zhaohui Zhang ◽

Xiang Zhu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Objective Response ◽

Acquired Resistance ◽

Small Cell ◽

Small Cell Lung ◽

Grade 3 ◽

Egfr Tki ◽

Egfr Tkis

e20529 Background: Acquired resistance to EGFR-TKIs frequently occurs in non-small cell lung cancer (NSCLC) patients (pts) with sensitizing EGFR mutations. EGFR-TKIs rechallenged therapy is one of the recommended strategies. This study aimed to explore the efficacy and safety of EGFR-TKI combined with apatinib (a TKI against VEGFR-2) in EGFR-TKIs resistant pts. Methods: From Aug 2015 to Nov 2016, we retrospectively screened 16 NSCLC pts who acquired resistance to the EGFR-TKI therapy and chose apatinib plus EGFR-TKI as the second-line treatment in our hospital. All pts signed informed consent before treatment. Results: Pts characteristics and efficacy are shown in the table below. Two pts discontinued on the 4th and 10th day due to side effects, respectively, and thus were excluded from short efficacy analysis. No CR, 4 PR and 10 SD were confirmed, resulting in an objective response rate of 28.6% and a disease control rate of 100%, respectively. At the cut-off date on Feb 7, 2017, 6 pts were still being treated. The median progression-free survival was 4.60 months (95%CI, 2.23–12.52 months). The main adverse events were hypertension, hand-foot skin reaction (HFSR) and diarrhea. Five (31.3%) grade 3 hypertension, 1 (6.3%) grade 3 HFSR and 1 (6.3%) grade 3 diarrhea were observed. Conclusions: EGFR-TKI combined with apatinib may stand for a new option for NSCLC pts with acquired EGFR-TKIs resistance. [Table: see text]

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