“In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.”
Keywords: lung cancer, brain metastases, capmatinib, resistance, MET
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In a new study, researchers investigated the effectiveness and safety of EGFR-tyrosine kinase inhibitors in elderly patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC).
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Lung cancer is a significant global health issue, being the second most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases and is often diagnosed at an advanced stage. Epidermal growth factor receptor (EGFR) mutations are more common in Asian NSCLC populations than in Western populations.
Activating EGFR mutations, such as exon 19 deletions and L858R, are predictive of response to tyrosine kinase inhibitors (TKIs) and have revolutionized the treatment landscape for patients with EGFR-mutated NSCLC. However, most clinical trials tend to lack data for the elderly population, even though a significant proportion of lung cancer patients are aged 65 years and older. This underrepresentation of elderly patients in clinical trials limits our understanding of the effectiveness and safety of EGFR-TKIs in this specific population.
“[…] comparisons of the effectiveness and safety of these EGFR-TKIs approved for patients aged ≥65 years are limited. The available real-world evidence for EGFR-TKI treatment of elderly patients is also limited. Therefore, this study aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients (aged ≥65 years) with EGFR-mutated advanced NSCLC.”
The Study
In this study, 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled from multiple hospitals in Taiwan. The patients were divided into four age groups: <65 years, 65-74 years, 75-84 years, and ≥85 years. Patient characteristics, including sex, smoking history, performance status, tumor involvement, EGFR mutation type, metastatic sites, and choice of EGFR-TKI, were compared among the age groups.
The researchers found that afatinib was more effective than gefitinib and erlotinib in elderly patients aged ≥65 years, as evidenced by longer median progression-free survival (PFS) and overall survival (OS). The median PFS for afatinib was 14.7 months, compared to 9.9 months for gefitinib and 10.8 months for erlotinib (p = 0.003). Similarly, the median OS for afatinib was 22.2 months, compared to 17.7 months for gefitinib and 18.5 months for erlotinib (p = 0.026).
Further analysis by age subgroup revealed that the significant differences in PFS and OS were primarily driven by patients aged 65-74 years. In this age group, afatinib demonstrated superior efficacy compared to gefitinib and erlotinib, with a median PFS of 14.7 months and median OS of 22.2 months (p = 0.032 for PFS, p = 0.018 for OS). While afatinib showed greater effectiveness, it was also associated with more adverse events (AEs) compared to gefitinib and erlotinib. The study reported a higher incidence of grade ≥3 AEs, including skin toxicities, paronychia, mucositis, and diarrhea, in patients receiving afatinib. Notably, patients receiving afatinib also required more dose reductions or discontinuation due to AEs.
Various factors were identified as independent prognostic factors of PFS and OS in elderly patients with EGFR-mutated advanced NSCLC. A performance status score of 2-4, stage IV disease, liver, bone, pleural, adrenal, and pericardial metastasis, and treatment with gefitinib were associated with worse PFS and OS.
Conclusion
This large retrospective study provides valuable real-world evidence on the effectiveness and safety of EGFR-TKIs in elderly patients with EGFR-mutated advanced NSCLC. The findings suggest that afatinib is more effective as a first-line treatment than gefitinib or erlotinib for elderly patients, particularly those aged 65-74 years. However, it is important to consider the increased risk of adverse events associated with afatinib in this population. These results highlight the need for individualized treatment decisions for elderly patients with NSCLC. Clinicians should carefully consider the patient’s age, performance status, and comorbidities when selecting an appropriate EGFR-TKI. Additionally, close monitoring of AEs and appropriate management strategies are crucial to ensure optimal treatment outcomes in this population.
“In conclusion, this study demonstrated the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that has often been underrepresented in clinical trials and real-world evidence. For elderly patients with EGFR-mutated advanced NSCLC, clinicians were more likely to prefer gefitinib or erlotinib to afatinib as a therapy, in contrast to the treatment regimen for younger patients. Nevertheless, afatinib still emerged as the primary choice for first-line treatment for older patients compared to other EGFR-TKIs, as it is more effective than gefitinib or erlotinib in elderly patients with EGFR-mutated advanced NSCLC.”
Click here to read the full research paper published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
In this new study, researchers investigated a plant used in traditional Chinese medicine and its anti-cancer effects in non-small cell lung cancer (NSCLC).
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Traditional Chinese medicine has long been explored for its potential in treating various diseases, including cancer. Lithospermum erythrorhizon, or purple gromwell, is a mysterious plant native to East Asia, and its dried root is often referred to as Zicao. Acetylshikonin, a compound derived from Zicao, has shown promise in exhibiting a variety of anti-cancer properties. While the effects of acetylshikonin on lung cancer are not yet fully understood, recent research has shed light on its potential as a therapeutic agent.
“This study explored the mechanisms underlying acetylshikonin-induced cell death in non-small cell lung cancer (NSCLC).”
Acetylshikonin and Cell Viability Reduction
In this study, researchers investigated the effects of acetylshikonin on the viability of NSCLC cells. The researchers treated H1299 and A549 cells with varying concentrations of acetylshikonin and assessed cell viability using a cell counting kit-8 (CCK-8) assay. The results showed that acetylshikonin significantly reduced cell viability in a dose-dependent manner. The IC50 values for H1299 and A549 cells were determined to be 2.34 μM and 3.26 μM, respectively. These findings suggest that acetylshikonin has the potential to effectively reduce the viability of lung cancer cells without causing significant damage to normal cells.
Cell Death Induction by Acetylshikonin
To further investigate the effects of acetylshikonin on NSCLC cells, the team examined the morphological changes associated with cell death. They observed that acetylshikonin treatment led to chromatin condensation, cell shrinkage, and the formation of cell debris, indicating cell death. Additionally, Annexin V/propidium iodide (PI) staining demonstrated an increase in the population of cells positive for Annexin V and PI, suggesting the induction of both apoptotic and necrotic cell death. Further analysis revealed that acetylshikonin increased membrane permeability, as evidenced by the uptake of PI by the cells. These findings indicate that acetylshikonin promotes cell death in NSCLC cells, potentially through necrotic pathways.
Acetylshikonin and Cell Cycle Arrest
In addition to its effects on cell viability and cell death, acetylshikonin was found to induce cell cycle arrest in NSCLC cells. The researchers examined the cell cycle progression of H1299 and A549 cells treated with acetylshikonin. Flow cytometry analysis revealed an increase in the proportion of cells in the subG1 and G2/M phases, indicating DNA fragmentation and cell cycle arrest in the G2/M phase. Western blot analysis further confirmed these findings by showing a decrease in the expression of cell cycle regulatory proteins, CDK1 and cyclin B1, in acetylshikonin-treated cells. These results suggest that acetylshikonin exerts its anti-cancer effects by inducing cell cycle arrest, thereby inhibiting cancer cell proliferation.
Oxidative Stress and Mitochondrial Dysfunction
The team also investigated the involvement of oxidative stress and mitochondrial dysfunction in acetylshikonin-induced cell death. Acetylshikonin treatment was found to increase intracellular reactive oxygen species (ROS) levels in NSCLC cells. This increase in ROS was associated with a decrease in mitochondrial membrane potential (MMP), indicating mitochondrial dysfunction. These findings suggest that acetylshikonin induces oxidative stress and disrupts mitochondrial function in NSCLC cells, potentially contributing to cell death.
Lipid Peroxidation and GPX4 Expression
The researchers explored the role of lipid peroxidation and the expression of glutathione peroxidase 4 (GPX4) in acetylshikonin-induced cell death. They observed that acetylshikonin treatment caused lipid peroxidation, as evidenced by the quenching of red fluorescence in BODIPY™ 581/591 C11-stained cells. This lipid peroxidation was associated with a decrease in GPX4 expression. GPX4 is an enzyme involved in maintaining cellular homeostasis and protecting against oxidative stress. The downregulation of GPX4 in NSCLC cells treated with acetylshikonin suggests a potential mechanism for inducing cell death.
Necroptosis Pathway Activation by Acetylshikonin
The team further investigated the mechanism by which acetylshikonin induces cell death in NSCLC cells. They found that acetylshikonin promoted the phosphorylation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like kinase (MLKL). These proteins are key players in the necroptosis signaling pathway. Immunofluorescence staining showed an increase in MLKL phosphorylation in acetylshikonin-treated cells, while Western blot analysis confirmed the activation of RIPK1, RIPK3, and MLKL. Importantly, pretreatment with RIPK1 inhibitors reversed the phosphorylation of MLKL and significantly attenuated cell death induced by acetylshikonin, suggesting that the activation of the RIPK1/RIPK3/MLKL cascade is involved in the necroptotic cell death pathway triggered by acetylshikonin.
Conclusion
In conclusion, acetylshikonin exhibits promising anti-cancer effects in NSCLC cells. It reduces cell viability, induces cell death, and promotes cell cycle arrest in the G2/M phase. Acetylshikonin also increases membrane permeability and activates the necroptosis signaling pathway through the phosphorylation of RIPK1, RIPK3, and MLKL. Furthermore, acetylshikonin induces oxidative stress, disrupts mitochondrial function, and promotes lipid peroxidation. These findings suggest that acetylshikonin holds potential as a therapeutic agent for the treatment of lung cancer. Further research is warranted to explore the clinical applications of acetylshikonin and its potential synergistic effects with existing lung cancer therapies.
“We determined that even low doses of acetylshikonin reduced the viability of lung cancer cells without significantly affecting normal cells. When used to treat lung cancer, acetylshikonin was shown to promote cell death and arrest cell cycle progression in the G2/M phase.”
Click here to read the full research paper published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
In this new study, researchers revealed a novel role for LGR6 in enhancing WNT signals in pancreatic cancer.
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Pancreatic cancer is one of the deadliest forms of cancer, with a very low survival rate and limited treatment options. Understanding the molecular mechanisms that drive the development and progression of this disease is crucial for finding new ways to prevent and treat it. One of the key players in pancreatic cancer is the WNT signaling pathway, which regulates many aspects of cell growth, differentiation and survival. WNT signaling is often dysregulated in pancreatic cancer, leading to uncontrolled cell proliferation, invasion and resistance to therapy.
“The canonical WNT pathway is reportedly an essential protagonist in organ development as well as oncogenesis in multiple cancers.”
LGR6 is a member of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, which can bind to proteins called R-spondins (RSPOs). RSPOs are known to potentiate WNT signaling by preventing the degradation of WNT receptors and co-receptors on the cell surface. The authors of this study note that LGR5 has previously been described as a WNT target gene as well as a marker of cancer stem cells. In this study, the team aimed to determine whether its homologue LGR6 incorporates similar functional aspects in pancreatic ductal adenocarcinoma (PDAC).
“In this work, we aimed to decipher the functions of LGR6 in WNT signaling of PDAC, apart from its assumed assignment as a receptor to RSPO. Taken into account the connections between WNT signaling and EMT, we further hypothesized a likely interplay of LGR6 and EMT.”
The researchers found that LGR6 is differentially expressed in various pancreatic cancer cell lines, depending on their phenotype and WNT activation status. Cell lines that have a more epithelial-like appearance and are more sensitive to WNT signals tend to express higher levels of LGR6 than cell lines that have a more mesenchymal-like appearance and are less responsive to WNT signals. Moreover, the researchers showed that adding RSPOs to the culture medium increased LGR6 expression in the epithelial-like cell lines, suggesting that there is a positive feedback loop between LGR6 and WNT signaling.
To investigate the functional role of LGR6 in pancreatic cancer, the researchers used small interfering RNAs (siRNAs) to knock down its expression in two epithelial-like cell lines. They found that reducing LGR6 levels decreased the activation of WNT signaling, as measured by the expression of WNT target genes and the accumulation of β-catenin, a key mediator of WNT signals. It is important to note that β-catenin is also a key mediator of epithelial–mesenchymal transition (EMT) — a process by which epithelial cells disconnect from each other and transdifferentiate into mesenchymal cells. Furthermore, the researchers observed that knocking down LGR6 impaired the ability of PDAC cells to form colonies in soft agar, a measure of their tumorigenic potential. It also reduced their capacity to form spheres in suspension, a measure of their stemness or self-renewal ability.
“Taken together, we present new evidence in PDAC that LGR6 might be a novel WNT target gene in this tumor. LGR6 seems to be involved in EMT and cancer stemness.”
Conclusions
This study sheds new light on the molecular mechanisms that modulate WNT signaling in pancreatic cancer and reveals a novel role for LGR6 as a WNT enhancer. Their results suggest that LGR6 is an important regulator of WNT signaling and stemness in pancreatic cancer cells, especially those with an epithelial phenotype. The authors propose that LGR6 may act as a switch that amplifies WNT signals in response to RSPOs, thereby enhancing the malignant properties of pancreatic cancer cells. They also speculate that LGR6 may have potential value for treatment stratification of pancreatic cancer patients, as its expression may indicate the responsiveness of tumors to therapies targeting WNT signaling.
“This knowledge could be applicable for detection and treatment of special subsets of pancreatic cancer cells. Further research is still needed to dissect the exact mechanisms under physiological as well as pathological conditions of benign and cancerous pancreatic cells.”
Click here to read the full study published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.