Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types.Cancers driven by gene fusion products tend to respond well to targeted therapies,where available;thus,detec...Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types.Cancers driven by gene fusion products tend to respond well to targeted therapies,where available;thus,detection of potentially targetable oncogenic fusions is necessary to select optimal treatment.Detection methods include non-sequencing methods,such as fluorescence in situ hybridization and immunohistochemistry,and sequencing methods,such as DNA-and RNA-based nextgeneration sequencing(NGS).While NGS is an efficient way to analyze multiple genes of interest at once,economic and technical factors may preclude its use in routine care globally,despite several guideline recommendations.The aim of this review is to present a summary of oncogenic gene fusions,with a focus on fusions that affect tyrosine kinase signaling,and to highlight the importance of testing for oncogenic fusions.We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions,and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers.Although treatment options may be limited for patients with rare alterations,healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.展开更多
Activating KRAS mutations are highly relevant to various cancers,and KRAS is the most frequently altered oncogenic protein in solid tumors.While historically considered undruggable,two KRASG12C inactive state-selectiv...Activating KRAS mutations are highly relevant to various cancers,and KRAS is the most frequently altered oncogenic protein in solid tumors.While historically considered undruggable,two KRASG12C inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer.However,these agents only demonstrate a 30–40%response rate and a median progression-free survival of approximately 6 months,with the inevitable emergence of resistance mechanisms,hence remaining far from achieving a cure.Additionally,several cancers with poor prognostic outcomes,such as pancreatic adenocarcinoma,are driven by other non-G12C KRAS mutations and thus have no effective targeted therapies.Improvements in understanding RAS signaling,RNA,and nucleic acid chemistry,as well as the role of the tumor microenvironment,have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies.In this review,we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS.We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies,describe their mechanisms of action,and offer insights into the current clinical trial status of each of these approaches.展开更多
文摘Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types.Cancers driven by gene fusion products tend to respond well to targeted therapies,where available;thus,detection of potentially targetable oncogenic fusions is necessary to select optimal treatment.Detection methods include non-sequencing methods,such as fluorescence in situ hybridization and immunohistochemistry,and sequencing methods,such as DNA-and RNA-based nextgeneration sequencing(NGS).While NGS is an efficient way to analyze multiple genes of interest at once,economic and technical factors may preclude its use in routine care globally,despite several guideline recommendations.The aim of this review is to present a summary of oncogenic gene fusions,with a focus on fusions that affect tyrosine kinase signaling,and to highlight the importance of testing for oncogenic fusions.We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions,and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers.Although treatment options may be limited for patients with rare alterations,healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.
文摘Activating KRAS mutations are highly relevant to various cancers,and KRAS is the most frequently altered oncogenic protein in solid tumors.While historically considered undruggable,two KRASG12C inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer.However,these agents only demonstrate a 30–40%response rate and a median progression-free survival of approximately 6 months,with the inevitable emergence of resistance mechanisms,hence remaining far from achieving a cure.Additionally,several cancers with poor prognostic outcomes,such as pancreatic adenocarcinoma,are driven by other non-G12C KRAS mutations and thus have no effective targeted therapies.Improvements in understanding RAS signaling,RNA,and nucleic acid chemistry,as well as the role of the tumor microenvironment,have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies.In this review,we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS.We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies,describe their mechanisms of action,and offer insights into the current clinical trial status of each of these approaches.
