scholarly journals Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

2018 ◽  
Author(s):  
Li Li ◽  
Yubo Wang ◽  
Lin Jiao ◽  
Caiyu Lin ◽  
Conghua Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Lung Cancer Patients ◽  
Knock Down ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Autophagy Inhibition ◽  
Resistant Cells

ABSTRACTDrug resistance to Osimertinib, a 3rd-generation EGFR-TKI is inevitable. Autophagy plays a contradictory role in resistance of 1stand 2ndgeneration EGFR-TKI, and its significance in osimertinib resistance is much less clear. We therefore investigated whether autophagy determines osimertinib resistance. First, osimertinib induced autophagy to a much greater extent than that of gefitinib, and autophagy inhibition further increased osimertinib efficacy. Next, enhanced autophagy was found in osimertinib resistant cells and autophagy inhibition partially reversed osimertinib resistance. Enhanced stem-cell like properties were found in resistant cells, and siRNA-knock down ofSOX2orALDH1A1reversed osimertinib resistance. Of note, autophagy inhibition or siRNA-knock down of Beclin-1 decreased expression of SOX2 and ALDH1A1 and stem-cell like properties. Next, autophagy inhibition and osimertinib in combination effectively blocked tumor growth in xenografts, which was associated with decreased autophagy and stem cell-like propertiesin vivo. Finally, enhanced autophagy was found in lung cancer patients with resistance to osimertinib. In conclusion, the current study delineates a previously unknown function of autophagy in determining osimertinib resistance through promoting stem-cell like properties.

CARD8/BCL-2 cascade in early adaptive drug resistant tumor escape against targeted inhibitors in NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22032-e22032
Author(s):  
Rakesh K. Bagai ◽  
Wei Zhang ◽  
Patrick Leahy ◽  
Lihong Yin ◽  
Patrick C. Ma
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Expression Analysis ◽  
Xenograft Model ◽  
Tumor Escape ◽  
Apoptosis Pathway ◽  
Egfr Tki ◽  
Resistant Cells

e22032 Background: Lung cancer targeted therapy is largely limited by inevitable recurrent resistant disease after initial response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), typically accompanied with divergent late acquired resistance mechanisms. We now focused on studying the emergence of early adaptive resistance to uncover attractive therapeutic targets to overcome drug resistance. Methods: HCC827 cells were treated with EGFR-TKI (0-9 days) with apoptosis pathway-specific QPCR array and TLVM analysis performed. MTS and crystal violet assays were performed. Western blot analysis was performed to examine prosurvival signaling developed against erlotinib, alone or in combination with MET inhibitor SU11274. IHC was performed on lung cancer tumor microarray (TMA) using BCL-2 and caspase-recruitment domain-containing protein 8 (CARD8) antibodies and graded (4 tier scoring system). NSCLC cell lines and murine xenograft models (HCC827, H1975) were developed for resistance biomarkers expression analysis in pre-/post-TKI treatment using anti-human CARD8, p-STAT3 and BCL-2 antibodies. Results: We characterized the emergence of early resistant lung cancer cells in escape against targeted TKIs with 100-fold higher IC50 in adaptive drug resistance. The resistant cells that evaded EGFR-TKI based targeted inhibition exhibited MET-independent induction of CARD8 and STAT3/BCL-2 mitochondrial prosurvival signaling in cellular quiescence, and inhibited cytoskeletal functions. Expression analysis studies demonstrated common tumor-associated expression of CARD8 but relatively low BCL-2 level in NSCLC. In vitro cell line studies suggest that CARD8 induction was preceded by a resurgence of STAT3 activation. In vivo xenograft model (HCC827/erlotinib; H1975/erlotinib+ SU11274) also verified upregulated CARD8/BCL-2 activation within early resistant cells. Conclusions: Resistant tumor cells that evaded EGFR inhibitors, alone or in combination with MET inhibitors, exhibited increased expression of CARD8-STAT3/BCL-2 prosurvival signaling cascade. Further studies to define the mechanism of CARD8 in promoting adaptive tumor drug resistance would be warranted.

scholarly journals Tumor Volume Decrease at 8 Weeks Is Associated with Longer Survival in EGFR-Mutant Advanced Non–Small-Cell Lung Cancer Patients Treated with EGFR TKI

2013 ◽  
Vol 8 (8) ◽  
pp. 1059-1068 ◽  
Author(s):  
Mizuki Nishino ◽  
Suzanne E. Dahlberg ◽  
Stephanie Cardarella ◽  
David M. Jackman ◽  
Michael S. Rabin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Tumor Volume ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Volume Decrease

scholarly journals Protein tyrosine kinase 2: a novel therapeutic target to overcome acquired EGFR-TKI resistance in non-small cell lung cancer

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Xuexia Tong ◽  
Ryosuke Tanino ◽  
Rong Sun ◽  
Yukari Tsubata ◽  
Tamio Okimoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Protein Tyrosine Kinase ◽  
Nsclc Cell ◽  
Tyrosine Kinase 2 ◽  
Tki Resistance ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Protein Tyrosine Kinase 2

Abstract Background Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target. Methods Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC cell lines. Results PTK2 was hyperphosphorylated in PC-9/PEM. Defactinib (PTK2 inhibitor) and PD173074 (FGFR inhibitor) inhibited PTK2 phosphorylation. Combination of PTK2 inhibitor and EGFR-TKI inhibited Akt and induced apoptosis in PC-9/PEM. The combination treatment showed improved in vivo therapeutic efficacy compared to the single-agent treatments. Furthermore, erlotinib-resistant NSCLC cell lines showed PTK2 hyperphosphorylation. PTK2 inhibition in the PTK2 hyperphosphorylated erlotinib-resistant cell lines also recovered EGFR-TKI sensitivity. Conclusion PTK2 hyperphosphorylation occurs in various EGFR-TKI-resistant NSCLCs. Combination of PTK2 inhibitor and EGFR-TKI (defactinib and osimertinib) recovered EGFR-TKI sensitivity in the EGFR-TKI-resistant NSCLC. Our study result suggests that this combination therapy may be a viable option to overcome EGFR-TKI resistance in NSCLC.

scholarly journals P3.02b-036 The Predictive Factors for Post-Progression Survival after EGFR-TKI Failure in Advanced EGFR-Mutant Lung Cancer Patients

2017 ◽  
Vol 12 (1) ◽  
pp. S1208-S1209
Author(s):  
Toshiki Ebisudani ◽  
Kei Nakashima ◽  
Masafumi Misawa ◽  
Akiko Tokumoto ◽  
Masahiro Nemoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Predictive Factors ◽  
Lung Cancer Patients ◽  
Egfr Mutant ◽  
Egfr Tki

scholarly journals P3.02b-026 Association of EGFR Exon 19 Deletion and EGFR-TKI treatment duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients

2017 ◽  
Vol 12 (1) ◽  
pp. S1201-S1202
Author(s):  
Norikazu Matsuo ◽  
Koichi Azuma ◽  
Kazuko Sakai ◽  
Akihiko Kawahara ◽  
Hidenobu Ishii ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Treatment Duration ◽  
T790m Mutation ◽  
Lung Cancer Patients ◽  
Exon 19 Deletion ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Exon 19

scholarly journals Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

2019 ◽  
Author(s):  
Yuetong Wang ◽  
Jian Zhang ◽  
Shengxiang Ren ◽  
Dan Sun ◽  
Hsin-Yi Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Metabolic Reprogramming ◽  
Tki Resistance ◽  
Combinational Treatment ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

SUMMARYDrug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR)-mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here we find that 2-hour sublethal TKI treatment elicits a transient drug-tolerant state in EGFR-mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated epigenetic upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combinational treatment with TKI and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with EGFR TKI response. Collectively, our findings reveal the importance of epigenetically regulated BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.HIGHLIGHTSSublethal EGFR TKI treatment induces transient drug-tolerant state and long-term resistance in EGFR-mutant lung cancer cellsEpigenetically regulated BCAT1-mediated metabolic reprogramming orchestrates EGFR TKI-induced drug resistanceCombinational treatment with TKI and ROS-inducing agents overcomes the drug resistance induced by EGFR TKI treatment

Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: Main challenges still to be overcome

2014 ◽  
Vol 40 (6) ◽  
pp. 723-729 ◽  
Author(s):  
J. Remon ◽  
T. Morán ◽  
N. Reguart ◽  
M. Majem ◽  
E. Carcereny ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Egfr Mutant ◽  
Egfr Tki

scholarly journals An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression

2021 ◽  
Author(s):  
Raffaella Sordella ◽  
Debjani Pal ◽  
Polona Safaric Tepes ◽  
Trine Lindsted ◽  
Ingrid Ibarra ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epigenetic Switch ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Oncogenic Mutations ◽  
A Cell ◽  
Egfr Tki ◽  
Related Mortality ◽  
Resistant Cells

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. Many lung cancer patients will develop resistance to chemotherapeutics. In the context of non-small cell lung cancers harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive Erlotinib resistance in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

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