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Cells
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Acquired Resistance and Malignant Progression of Lung Adenocarcinoma
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Acquired Resistance and Malignant Progression of Lung Adenocarcinoma

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (1 September 2021) | Viewed by 14117

Special Issue Editor

Dr. Yoshinori Murakami

E-Mail Website
Guest Editor
Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Interests: cell adhesion; invasion and metastasis; genome analysis; development of novel approaches to diagnosis and treatment of cancer

Special Issue Information

Dear colleagues,

Lung adenocarcinoma is the most common subtype of lung cancer. Thanks to the advances in molecular oncology, a number of driver genes have been identified in lung adenocarcinoma, and appropriate inhibitors have been developed against each molecular target. Now, lung adenocarcinoma is the best solid cancer to which targeted therapy is established and clinically available. However, tumors resistant against targeted drugs develop frequently, providing the biggest challenge in current treatment of lung cancer. Fortunately, this problem is also being overcome by elucidating the mechanisms of resistance and developing the next generation of targeted drugs, which are designed to overcome initial resistance. At present, two resistance mechanisms are demonstrated clearly in lung adenocarcinoma; on-target resistance, in which a targeting protein itself is mutated, and off-target resistance, in which downstream or parallel pathways are activated. Furthermore, changes in cellular context or lineage, such as epithelial–mesenchymal transition and SCLC transition, are reported to be possible additional mechanisms for resistance against EGFR-tyrosine kinase inhibitors, suggesting that acquired resistance could be associated with invasion and metastasis in advanced lung adenocarcinoma. In fact, it is convincing that invasion and metastasis, which cause over 90% of direct cancer death in solid tumors, are another big target for treatment of lung adenocarcinoma. However, no available drugs against cancer invasion and metastasis are currently developed partly due to the complexity of signaling, spreading to the whole body, and difficulty in assessment of the inhibitory effect in invasion and metastasis. Thus, elucidation of cell signaling involved in resistance, invasion, and metastasis by novel approaches and development of multidisciplinary treatment are prerequisites to overcome lung adenocarcinoma. The primary focus of this topic will be cell signaling and context in acquired resistance of lung adenocarcinoma against targeted therapy. In addition, the reviews and original articles will explore the mechanisms and signaling of cancer invasion and metastasis from the viewpoint of malignant progression and resistance to the treatment of lung adenocarcinoma.

Dr. Yoshinori Murakami
Guest Editor

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Keywords

  • lung adenocarcinoma
  • driver gene
  • signaling
  • molecular targeted therapy/drug
  • acquired resistance
  • cell context
  • epithelial mesenchymal transition
  • cancer invasion and metastasis
  • multidisciplinary treatment

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Published Papers (3 papers)

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Research

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14 pages, 3290 KiB  
Article
Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines
by Wonjun Ji, Yun Jung Choi, Myoung-Hee Kang, Ki Jung Sung, Dong Ha Kim, Sangyong Jung, Chang-Min Choi, Jae Cheol Lee and Jin Kyung Rho
Cells 2020, 9(12), 2596; https://doi.org/10.3390/cells9122596 - 3 Dec 2020
Cited by 18 | Viewed by 4444
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Acquired Resistance and Malignant Progression of Lung Adenocarcinoma)
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Review

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12 pages, 508 KiB  
Review
Current Therapeutic Strategies and Prospects for EGFR Mutation-Positive Lung Cancer Based on the Mechanisms Underlying Drug Resistance
by Yukari Tsubata, Ryosuke Tanino and Takeshi Isobe
Cells 2021, 10(11), 3192; https://doi.org/10.3390/cells10113192 - 16 Nov 2021
Cited by 20 | Viewed by 4193
Abstract
The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is [...] Read more.
The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is common in East Asia, and approximately 50% of adenocarcinomas harbor EGFR mutations. Undoubtedly, EGFR-TKIs, with their promising efficacy, are the mainstay of primary therapy. However, even if tumor shrinkage is achieved, most patients become resistant to EGFR-TKIs and relapse; hence, EGFR-TKIs do not achieve a radical cure. The problem of the development of resistance to targeted drugs has been a persistent challenge. After the role of EGFR T790M mutation in acquired drug resistance was reported, osimertinib, a third-generation irreversible EGFR-TKI, was designed to overcome the resistance conferred by T790M mutation. In addition, some studies have reported the mechanism of drug resistance caused by mutations other than the T790M mutation and strategies to overcome them. Elucidating the mechanism underlying drug resistance development and combining therapeutic approaches are expected to further improve NSCLC prognosis. Full article
(This article belongs to the Special Issue Acquired Resistance and Malignant Progression of Lung Adenocarcinoma)
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Other

Jump to: Research, Review

9 pages, 629 KiB  
Brief Report
EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios
by Ikei S. Kobayashi, Hollis Viray, Deepa Rangachari, Susumu S. Kobayashi and Daniel B. Costa
Cells 2021, 10(12), 3561; https://doi.org/10.3390/cells10123561 - 17 Dec 2021
Cited by 13 | Viewed by 4816
Abstract
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of [...] Read more.
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and mobocertinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration. Full article
(This article belongs to the Special Issue Acquired Resistance and Malignant Progression of Lung Adenocarcinoma)
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