scholarly journals From Biology to Therapy: Improvements of Therapeutic Options in Lung Cancer

2019 ◽  
Vol 18 (9) ◽  
pp. 1235-1240 ◽  
Author(s):  
Luigi Formisano ◽  
Valerie M. Jansen ◽  
Roberta Marciano ◽  
Roberto Bianco
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
In Vivo Models ◽  
Egfr Tyrosine Kinase Inhibitors

Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In “in vitro” and “in vivo” models of NSCLC (Non-Small Cell Lung Cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (Epithelial Growth Factor Receptor) mutations that predict sensitivity to the anti-EGFR Tyrosine Kinase Inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intratumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (Programmed Death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor.

scholarly journals Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhimin Zhang ◽  
Xiaojuan Lian ◽  
Wei Xie ◽  
Jin Quan ◽  
Maojun Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Advanced Lung Cancer ◽  
Tki Resistance ◽  
Geo Dataset ◽  
Epidermal Growth

AbstractResistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

scholarly journals Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

2021 ◽  
Author(s):  
Aya Shiba-Ishii ◽  
Ted W Johnson ◽  
Ibiayi Dagogo-Jack ◽  
Mari Mino-Kenudson ◽  
Theodore R Johnson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Precision Oncology ◽  
Resistance Mutations ◽  
In Vivo Models ◽  
Alk Positive

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mutations was achieved primarily through two different mechanisms of improved targeting of either G1202R- or I1171N/S/T-mutant kinases. Based on these results, we propose a classification of heterogenous ALK compound mutations designed to focus the development of distinct therapeutic strategies for precision targeting of compound resistance mutations following sequential TKIs.

scholarly journals Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Nan Yao ◽  
Chen-Ran Wang ◽  
Ming-Qun Liu ◽  
Ying-Jie Li ◽  
Wei-Min Chen ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Recycling Endosome ◽  
Egfr Activation ◽  
Survival Pathways ◽  
Egfr Ligand ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

Abstract Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

scholarly journals Therapeutic Application of Brain-Specific Angiogenesis Inhibitor 1 for Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3562
Author(s):  
Mitra Nair ◽  
Chelsea Bolyard ◽  
Tae Jin Lee ◽  
Balveen Kaur ◽  
Ji Young Yoo
Keyword(s):  
Angiogenesis Inhibitor ◽  
Suppressor Gene ◽  
Chemotherapeutic Agents ◽  
Tumor Models ◽  
In Vivo Models ◽  
Herpes Simplex Viruses ◽  
Multiple Tumor ◽  
And Function

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1) is an adhesion G protein-coupled receptor that has been found to play key roles in phagocytosis, inflammation, synaptogenesis, the inhibition of angiogenesis, and myoblast fusion. As the name suggests, it is primarily expressed in the brain, with a high expression in the normal adult and developing brain. Additionally, its expression is reduced in brain cancers, such as glioblastoma (GBM) and peripheral cancers, suggesting that BAI1 is a tumor suppressor gene. Several investigators have demonstrated that the restoration of BAI1 expression in cancer cells results in reduced tumor growth and angiogenesis. Its expression has also been shown to be inversely correlated with tumor progression, neovascularization, and peri-tumoral brain edema. One method of restoring BAI1 expression is by using oncolytic virus (OV) therapy, a strategy which has been tested in various tumor models. Oncolytic herpes simplex viruses engineered to express the secreted fragment of BAI1, called Vasculostatin (Vstat120), have shown potent anti-tumor and anti-angiogenic effects in multiple tumor models. Combining Vstat120-expressing oHSVs with other chemotherapeutic agents has also shown to increase the overall anti-tumor efficacy in both in vitro and in vivo models. In the current review, we describe the structure and function of BAI1 and summarize its application in the context of cancer treatment.

scholarly journals Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

2021 ◽  
Author(s):  
Fatemah Bahman ◽  
Valeria Pittalà ◽  
Mohamed Haider ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Triple Negative Breast Cancer ◽  
Tyrosine Kinases ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

scholarly journals TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 868
Author(s):  
Florian Drescher ◽  
Patricia Juárez ◽  
Danna L. Arellano ◽  
Nicolás Serafín-Higuera ◽  
Felipe Olvera-Rodriguez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Kinase Inhibitors ◽  
Disseminated Tumor Cells ◽  
Tyrosine Kinase Receptor ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Cell Dormancy

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.

scholarly journals Hyaluronate Functionalized Multi-Wall Carbon Nanotubes Filled with Carboplatin as a Novel Drug Nanocarrier against Murine Lung Cancer Cells

Nanomaterials ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 1572 ◽  
Author(s):  
Daniel Salas-Treviño ◽  
Odila Saucedo-Cárdenas ◽  
María de Jesús Loera-Arias ◽  
Humberto Rodríguez-Rocha ◽  
Aracely García-García ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Carbon Nanotubes ◽  
Tumor Cells ◽  
Therapeutic Potential ◽  
Cell Uptake ◽  
In Vivo Models ◽  
Multi Wall Carbon Nanotubes ◽  
Lung Cancer Model

Carbon nanotubes (CNTs) have emerged in recent years as a potential option for drug delivery, due to their high functionalization capacity. Biocompatibility and selectivity using tissue-specific biomolecules can optimize the specificity, pharmacokinetics and stability of the drug. In this study, we design, develop and characterize a drug nanovector (oxCNTs-HA-CPT) conjugating oxidated multi-wall carbon nanotubes (oxCNTs) with hyaluronate (HA) and carboplatin (CPT) as a treatment in a lung cancer model in vitro. Subsequently, we exposed TC–1 and NIH/3T3 cell lines to the nanovectors and measured cell uptake, cell viability, and oxidative stress induction. The characterization of oxCNTs-HA-CPT reveals that on their surface, they have HA. On the other hand, oxCNTs-HA-CPT were endocytosed in greater proportion by tumor cells than by fibroblasts, and likewise, the cytotoxic effect was significantly higher in tumor cells. These results show the therapeutic potential that nanovectors possess; however, future studies should be carried out to determine the death pathways involved, as well as their effect on in vivo models.

scholarly journals Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1550 ◽  
Author(s):  
Tomomi Sanomachi ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
Shizuka Seino ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
Underlying Mechanisms

Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

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