A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response ...to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression ...and its regulation in NSCLC positive for the EML4-ALK fusion gene.
The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis.
The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens.
Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. ...Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.
This retrospective study aimed to identify predictors for the development of palbociclib-induced neutropenia. This study retrospectively analysed 78 breast cancer patients who had received ...palbociclib at our hospital between January 2018 and May 2020. For the regression analysis of factors associated with palbociclib-induced neutropenia, variables were extracted manually from medical charts. The level of palbociclib-induced neutropenia was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 5). Multivariate ordered logistic regression analysis was performed to identify predictors for the development of neutropenia. Optimal cut-off thresholds were determined using receiver operating characteristic (ROC) analysis. Values of P < 0.05 (2-tailed) were considered significant. Significant factors identified included concomitant use of statin (odds ratio OR = 0.104, 95% confidence interval CI = 0.018-0.598; P = 0.011) and body mass index (BMI) (OR = 1.118, 95% CI = 1.007-1.241; P = 0.037). ROC analysis revealed that neutropenia (grade 4) was more likely to occur with a BMI ≥ 22.3 kg/m
. In conclusion, no concomitant use of statins and high BMI were identified as significant predictors for the development of palbociclib-induced neutropenia.
Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, ...resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents.
BackgroundOxaliplatin causes acute cold-induced neurotoxicity and chronic cumulative neuropathy, which can require dose modification and impacts quality of life. However, effective strategies for ...managing oxaliplatin-induced peripheral neuropathy (OIPN) among affected patients remain elusive.ObjectiveThis retrospective study aimed to identify predictors for the development of OIPN.MethodsParticipants comprised 322 cancer patients at our hospital who were receiving oxaliplatin between January 2017 and March 2021. For the regression analysis of factors associated with OIPN, variables were manually extracted from medical charts. The severity of OIPN was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of OIPN. Optimal cut-off thresholds were determined using receiver operating characteristic analysis. Values of P <0.05 (2-tailed) were considered significant.ResultsSignificant risk factors identified included higher body mass index (BMI) (odds ratio OR = 1.06, 95% confidence interval CI = 1.00-1.12; P = 0.043), female sex (OR = 1.67, 95%CI = 1.06-2.61; P = 0.026) and higher total dosage (OR = 2.39, 95%CI = 1.67-3.42; P = < 0.0001).ConclusionHigh BMI, female sex and high total dosage were identified as significant predictors for the development of OIPN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oxaliplatin causes acute cold-induced neurotoxicity and chronic cumulative neuropathy, which can require dose modification and impacts quality of life. However, effective strategies for managing ...oxaliplatin-induced peripheral neuropathy (OIPN) among affected patients remain elusive. This retrospective study aimed to identify predictors for the development of OIPN. Significant risk factors identified included higher body mass index (BMI) (odds ratio OR = 1.06, 95% confidence interval CI = 1.00-1.12; P = 0.043), female sex (OR = 1.67, 95%CI = 1.06-2.61; P = 0.026) and higher total dosage (OR = 2.39, 95%CI = 1.67-3.42; P = < 0.0001). High BMI, female sex and high total dosage were identified as significant predictors for the development of OIPN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This retrospective study was undertaken to identify predictors for the development of hypocalcaemia even with prophylactic administration of calcium and vitamin D, and to help guide future strategies ...to improve the safety, efficacy, and QOL of patients receiving denosumab. Between January 2016 and February 2020, a total of 327 advanced cancer patients at our hospital who were receiving denosumab were enrolled. Variables associated with the development of hypocalcaemia were extracted from the clinical records. The level of hypocalcaemia was evaluated using CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of hypocalcaemia. Optimal cut off thresholds were determined using ROC analysis. Values of P < 0.05 (2-tailed) were considered significant. 54 patients have developed hypocalcemia (≥ Grade 1). Significant factors identified included concomitant use of vonoprazan odds ratio (OR) = 3.74, 95% confidence interval (CI) 1.14-12.26; P = 0.030, dexamethasone (OR = 2.45, 95%CI 1.14-5.42; P = 0.022), pre-treatment levels of serum calcium (OR = 0.27, 95%CI 0.13-0.54; P < 0.001), ALP/100 (OR = 1.04, 95%CI 1.01-1.07; P = 0.003), and haemoglobin (OR = 0.79, 95%CI 0.68-0.93; P = 0.004). ROC curve analysis revealed that the threshold for pre-treatment levels of serum calcium was ≤ 9.3 mg/dL, ALP was ≥ 457 U/L, and haemoglobin was ≤ 10.4 g/dL. In conclusion, concomitant use of vonoprazan or dexamethasone, and pre-treatment levels of serum calcium (low), ALP (high) and haemoglobin (low) were identified as significant predictors for the development of denosumab-induced hypocalcaemia.
Background
Cachexia, a disorder associated with anorexia, inflammation, and muscle wasting, is frequent in cancer patients. We performed post‐hoc analyses of the ONO‐7643‐04 study to investigate the ...efficacy and safety of anamorelin in subgroups of Japanese patients with non‐small cell lung cancer (NSCLC).
Methods
The patients were divided into subgroups by baseline characteristics, including sex, age, body mass index, prior weight loss, performance status (PS), concomitant anticancer therapy, and number of previous chemotherapy regimens. The changes from baseline through to 12 weeks for lean body mass (LBM), body weight, and appetite were calculated. Appetite was evaluated using the quality of life questionnaire for cancer patients treated with anticancer drugs (QOL‐ACD) item 8 score. Responder rates were defined as the maintenance/improvement of LBM (≥0 kg), body weight (≥0 kg), or QOL‐ACD item 8 score (≥0) from baseline to all evaluation time points. Safety was evaluated in patients subgrouped by age and PS.
Results
Anamorelin resulted in greater improvements versus placebo in LBM, body weight, and appetite in most subgroups. Anamorelin was also associated with greater LBM, body weight, and appetite responder rates than placebo in nearly all subgroups. Among anamorelin‐treated patients, adverse drug reactions (ADRs) tended to be more frequent with increasing age (<65 years, 19.2%; ≥65 to <75 years, 45.9%; ≥75 years, 60.0%) and PS score (PS 0–1, 38.4%; PS 2, 60.0%). The frequency of serious ADRs was 2.7% and 0% in the PS 0–1 and PS 2 subgroups, respectively.
Conclusion
This study of NSCLC patients with cancer cachexia revealed consistent improvements in LBM, body weight, and appetite across most subgroups of anamorelin‐treated patients. This study also demonstrated the tolerability of anamorelin regardless of age and PS, with a low incidence of serious ADRs in each subgroup.
We performed post‐hoc analyses of the ONO‐7643‐04 study to investigate the efficacy and safety of anamorelin in subgroups of Japanese patients with non‐small cell lung cancer. This study revealed consistent improvements in lean body mass, body weight, and appetite score using QOL‐ACD item 8 across most subgroups of anamorelin‐treated patients versus placebo. This study also demonstrated the tolerability of anamorelin regardless of age and performance status, with a low incidence of serious adverse drug reactions in each subgroup.
The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune ...checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.