Effect of PRMT5i (MRTX1719), ERKi (Adagrasib), RAFi (Belvarafenib) and their combination on non-small cell lung cancer cell line (LU99)
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ABSTRACT:
PROVIDER: PRJNA1190433 | ENA |
REPOSITORIES: ENA
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Project description:Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor has become one of the important treatment options for patients with advanced non-small cell lung cancer (NSCLC). However, only a small subset of patients with NSCLC can currently receive single-agent PD-1 inhibitors as first-line therapy, for the limitations of population selection exclude most patients from immuno-oncology (IO) monotherapy. In order to expand the candidate population for IO first-line treatment and make more newly diagnosed patients benefit from IO treatment, a series of studies are focusing on the combination of IO and other drugs in NSCLC. We reviewed the latest clinical data of IO first-line combination therapy in recent years, suggesting that on the basis of PD-1/PD-L1 inhibitors, combined with other IO, chemotherapy, anti-angiogenic drugs, targeted therapy or radiotherapy may produce synergistic anti-tumor effects. It is expected to benefit more newly diagnosed patients.?.
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Project description:CDKN2A/MTAP co-deletion occurs frequently in non-small cell lung cancer and other solid tumors including glioblastoma and pancreatic ductal adenocarcinoma. Lung cancer remains the leading cause of cancer-related mortalities and fewer than 15% of glioblastoma or pancreatic cancer patients survive 5 years underscoring the need for more effective therapies. PRMT5 is a synthetic-lethal dependency in MTAP null tumors and an attractive therapeutic target for CDKN2A/MTAP deleted cancers. A new revolutionary class of inhibitors, referred to as MTA-cooperative PRMT5 inhibitors, has shown promising results in ongoing early phase clinical trials. Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation of other pathways could improve the efficacy of MTA-cooperative PRMT5 inhibitors. Using a paralog and single gene targeting CRISPR library we screened MTAP deleted cancers in the presence or absence of PRMT5 inhibitors. We identified several genes sensitizing to PRMT5 inhibition including members of the MAP kinase pathway. We demonstrate that genetic depletion or chemical inhibition of MAP kinase pathway members using KRAS, MEK, ERK, and RAF inhibitors synergize with PRMT5 inhibition to kill CDKN2A/MTAP null, RAS-active tumors. Further, PRMT5 inhibitors combined with either KRAS or RAF inhibitors durable in vivo complete responses, emphasizing the potential benefit for patients.
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Project description:MiaPaCa-2 xenografts SHP2i + ERKi
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Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. To be able to better understand the differences in response between individual cells, we performed treatment of PC9 cells grown in cell culture with etoposide, erlotinib and its combination with crizotinib, followed by Drop-seq. The addition of crizotinib was guided by our previous data that an erlotinib-resistant drug population may be sensitive to crizotinib. To better understand the common events in drug resistance, we compared the resistant cell populations arising from the treatment with etoposide and from the treatment with erlotinib. The results of our study will address emerging drug resistance that limits clinical usefulness of conventional and targeted strategies, particularly in NSCLC.
2020-12-19 | GSE149215 | GEO
Project description:Profiling non-small cell lung carcinoma cell line PC9 treated with etoposide, erlotinib and its combination with crizotinib
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Project description:RATIONALE: AZD2171 may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving AZD2171 together with standard combination chemotherapy may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of AZD2171 when given together with standard combination chemotherapy in treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer.
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Project description:Background. Novel combination therapies with PD-1/PD-L1 inhibitors are needed to overcome resistance to these drugs. Bezafibrate, a ligand of PGC-1a/PPAR complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase I trial of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through upregulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.
2025-05-06 | GSE202417 | GEO
Project description:Immune checkpoint inhibitors enhance the activation and antitumor activity of the immune system, resulting in durable response rates in a select group of patients. Cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors target the inhibitory interaction between CTLA4 and CD80 or CD86. Programmed death 1 (PD1) inhibitors target the interaction between PD1 receptors on T-cells and PD-ligand 1 (PD-L1) and PD-ligand 2, blocking the inhibitory signaling and resulting in activation of T-cell effector function. These therapeutic drugs were originally evaluated in patients with metastatic melanoma before expansion to all tumor types, including non-small cell lung cancer (NSCLC) with promising results. The PD1 inhibitors such as pembrolizumab have now received FDA approval in the first-line setting for patients with positive PD-L1 expression tumor types; however, only a portion of patients have shown objective and sustainable responses. To expand the number of patients with observed response to immunotherapeutic agents including patients with negative PD-L1 expression tumors, clinical trials are ongoing to assess the safety and efficacy of combination immune checkpoint inhibitors and combination immune checkpoint inhibitors with targeted therapy. Immune checkpoint inhibitors have been found to be a promising therapeutic drug class with sustainable response rates and a tolerable safety profile, and efforts continue to improve these drugs in patients with NSCLC.
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Project description:BackgroundImmune-based combination therapies have revolutionized the first-line treatment for advanced non-small cell lung cancer (NSCLC). However, for the efficacy and safety, the best treatment option is still uncertain.MethodsWe conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) to evaluate first-line immune-based combination therapies for advanced NSCLC.ResultsFourteen trials involving 8467 patients were included. For the programmed cell death-ligand 1 (PD-L1) expression non-selective patients, there were no significant differences among all the treatment modes for overall survival (OS), but the ranking profiles indicated that Immunotherapy + Immunotherapy + Chemotherapy (IO + IO + Chemo) was most likely to be the best mode (probability = 68%). Immunotherapy + Immunotherapy + Anti-angiogenic therapy + Chemotherapy (IO + Anti-angio + Chemo) was significantly better than most other treatment modes for progression-free survival (PFS) with better objective response rate (ORR) and more obvious grade ≥3 treatment-related adverse events (TRAEs). In PD-L1-high cohort, IO + Anti-angio + Chemo seemed to be the best mode for OS, PFS, and ORR according to the ranking profiles. In PD-L1-intermediate and PD-L1-negative cohort, IO + IO + Chemo was inclined to be ranked first for prolonging OS (probability = 78%; 37%) and IO + Anti-angio + Chemo was most likely to provide best PFS (probability = 96%; 100%).ConclusionIO + IO + Chemo has great potential to improve the OS regardless of histology type, especially in PD-L1-intermediate and PD-L1-negative cohort. IO + Anti-angio + Chemo shows great superiority in improving the short-term survival accompanied by increasing grade ≥3 TRAEs.
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