KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targete...KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targeted recently.Several covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.However,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable.It is of great importance to discover biomarkers to distinguish patients who are likely benefitted.Moreover,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies.Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical settings.This review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.展开更多
Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer therapy.In this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were design...Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer therapy.In this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized.All the new derivatives were tested by p110α enzymatic and Rh30 cellular assays.Further enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.展开更多
Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance pos...Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance poses a significant clinical challenge.Loss of PTEN and activation of mTOR,CDK4/6,or PIM have been reported to mediate acquired resistance to alpelisib.4,5,6,7 The mechanisms leading to resistance to PI3Kαinhibitors appear to be different under different circumstances,and the aforementioned strategies may be beneficial for a particular group of patients.New strategies to overcome acquired resistance in a broad spectrum of patients need to be discovered.展开更多
基金supported by the National Natural Science Foundation of China(No.81773760,81973345,and 82104199).
文摘KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging.Among the different known mutants,KRas^(G12C) has been proved to be successfully targeted recently.Several covalent inhibitors selectively targeting KRas^(G12C) have shown promising efficacy against cancers harboring KRAS G12C mutation in clinical trials and AMG510(sotorasib)has been approved for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.However,the overall responsive rate of KRas^(G12C) inhibitors was around 50%in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable.It is of great importance to discover biomarkers to distinguish patients who are likely benefitted.Moreover,adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies.Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRas^(G12C) inhibitors in preclinical settings.This review summarized the recent progress of covalent KRas^(G12C) inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.
基金the National Natural Science Foundation of China(Nos.81273365 and 81321092)Chinese National Science&Technology Major Project "Key New Drug Creation and Manufacturing Program"(Nos.2012ZX09103101-024 and 2014ZX09304002-008-001)+1 种基金Chinese National Programs for High Technology Research and Development(No.2012AA020302)the Shanghai Science and Technology Commission(Nos.11431921100 and 12DZ1930802)for their financial support
文摘Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer therapy.In this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized.All the new derivatives were tested by p110α enzymatic and Rh30 cellular assays.Further enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.
文摘Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance poses a significant clinical challenge.Loss of PTEN and activation of mTOR,CDK4/6,or PIM have been reported to mediate acquired resistance to alpelisib.4,5,6,7 The mechanisms leading to resistance to PI3Kαinhibitors appear to be different under different circumstances,and the aforementioned strategies may be beneficial for a particular group of patients.New strategies to overcome acquired resistance in a broad spectrum of patients need to be discovered.
