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    Home > Medical News > Latest Medical News > The road to the KRAS Iron Throne, Gacus takes the lead in China

    The road to the KRAS Iron Throne, Gacus takes the lead in China

    • Last Update: 2020-07-29
    • Source: Internet
    • Author: User
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    RaS gene mutations are genetic drivers for a variety of cancer types, including colorectal cancer, pancreatic catheteradenal cancer (PDAC), lung adenocarcinoma (LUAD; a subtype of non-small cell lung cancer (NSCLC), melanoma, and certain blood system cancers1 Isomers (KRAS, NRAS, or HRAS), ciphers, and frequencies of tissue distribution RAS mutations vary by tissue typeFor example, a large percentage of LUAD (32%), PDAC (86%) and CRC (41%) are driven by KRAS mutations, in which the KRAS mutation occurs primarily in the 12th-digit cipherBy contrast, 29% of melanomas are driven by NRAS mutations, which, unlike KRAS, occur in crypto61HRAS mutations occur less frequently than KRAS or NRAS mutations, but a small fraction of head and neck squamous cell carcinoma (HNSCC; 5%) and bladder cancer (6%) are driven by HRAS mutations, which occur in ciphers 12 or 61As shown in Figure 1 belowFigure 1Frequency and distribution of RAS gene mutations in human cancers -aThe distribution of RAS subtypes (KRAS, NRAS and HRAS) mutations in different tumor types and the frequency of RAS subtype mutations in each tumor type; The percentage of KRAS mutations in the 12th cryptosome of RAS common mutation tissue, and the percentage of NRAS mutations of the 61st cryptoon of melanoma, the biochemical properties of the 2 mutant RAS Normally, mutations of the cryptosis 12 will destroy the GTPase activity of RAS, thereby reducing the hydrolysis rate of THE GTP, so the mutant protein accumulates in the state of GTP bindingThe mutation of the 61-bit crypt speeds up the GDP-GTP exchange and reduces the hydrolysis speed of gtP, so the RAS mutantof of the 61-bit crypt will also accumulate in the combined state of the GTP, as shown in Figure 2 belowTHE COMBINED RAS OF GTP ACTIVATES THE DOWNSTREAM EFFECT PATHWAY AND PROMOTES CELL PROLIFERATION, MOST NOTABLY THE MAPK AND PI3K PATHWAYSFigure 2Overview of the general biochemical interference of hydrolysis and ostrich exchange caused by the cryptin 12 or 61 mutationsOf the 13 patients who received a target dose of 960 mg, 7 were partially remissionary (PR), 6 were stable (SD), and the disease control rate was 100%Good safety and toleranceThe specific results include security figures 3, 4, and 5 belowFigure 3 Assessable Patients with Post-Baseline Tumor Data (N-22),Source:Public Information Collating Figure 4 Recommended to Phase II Dose 960 mg AMG510 For Current Efficacy,Source:Public Information Collating Figure 5 Summary of adverse events (AEs) in Patients with AMG-510,Source:Public Information Collating It is important to note that AMG510 is much less active in colorectal cancer: only 1 in 12 patients had PR and 10 had SD B MRTX849 Data from the first 12 patients with advanced lung and colorectal cancer assessed (17 in the first phase trial) showed that 40% of patients had significantly reduced tumor size Three patients with advanced lung cancer had partial reactions (tumor volume decreased by 30% or more) One of the patients with advanced colorectal cancer who was assessed had a partial response All patients who responded received the highest dose used in the dose range study (twice a day at 600 mg) Most of the side effects of MRTX-849 were reported to be mild, including diarrhea and nausea; The results are shown in Figures 6 and 7 below Figure 6 MRTX849 is currently publicly available for efficacy, data source: Public Information Collating Figure 7 Summary of adverse events (AEs) in patients with MRTX849, Source: Public Information Collating C Other Small Molecular Inhibitors in Clinical Phase Table 1 Other Small Molecular Inhibitors in Clinical Phase Sydment Symita Source: Drug Bank ARS-3248 is a new generation of KRAS G12C inhibitors developed on the basis of ARS-1620 In May 2019, Wellspring announced that the FDA had approved THE IND application for ARS-3248 Janssen is solely responsible for the clinical development of the compound and registered JNJ-74699157 (ARS-3248) in clinical trials on July 26 to conduct a phase I trial (NCT04006301) in patients with positive advanced stage stage solid tumors in the kraSG12C group On September 29, 2019, JAB-3312, a small molecule oral anti-tumor drug with global intellectual property rights developed independently by the domestic company Gacos, was granted clinical license in China JAB-3312 will be used to treat patients with genotype abnormally active tumors such as KRAS G12, BRAFClass3, NF1LoF, and RTK mutations, amplification or rearrangement, including, but not limited to, non-small cell lung cancer, colorectal cancer, pancreatic cancer, esophageal scale cancer, head and neck scale cancer BI1701963 inhibits KRAS by combining with SOS1 By swapping RAS-bound GDP for GTP, SOS1 can help activate KRAS Selective suppression of SOS1 is a therapeutic concept that enables KRAS blocking regardless of the type of KRAS mutation Preclinical studies show that pan-KRAS inhibitors inhibit the growth of multiple G12 and G13 KRAS gene mutant tumors (the most commonly affected protein residues) D Combination therapy is also being developed for both upstream and downstream targets of the KRAS and KRAS signaling pathways, as detailed in Table 2 Table 2 Joint treatment sedatives containing KRAS in clinical development Source: Drug Crossing Database, Public Information Collection Researchers combined KRAS inhibitors with CDK, EGFR, Tubulin, MEK and other inhibitors to expect therapeutic synergies in the body 4 Existing problems I Allelgenest gene-specific inhibitors may have limited efficacy as monotherapy The largest anti-tumor effects need to be combined with other inhibitors, but it can be challenging to determine which combination strategy works best in patients II Tumor types can significantly affect response rates Early data from the AMG510 trial showed that colorectal cancer is more difficult to treat than LUAD, suggesting that colorectal cancer will require combination treatment The treatment of colorectal cancer is particularly challenging III Historically, combination therapy has been toxic and inpoor safety However, the toxicity of the lack of dose limit seispha observed by AMG510 is encouraging, and mutation-specific therapy should have limited non-target effects Isonostogenesis inhibitors (low toxic) can be used in combination with other more toxic inhibitors without the problem of combining two toxic compounds observed when using pi3K and MEK inhibitors IV As the treatment of RAS-driven tumors becomes more personalized, the potential resistance mechanism sized by allele gene needs to be evaluated 5 Summarizing KRAS-G12C alleles gene-specific inhibitors will change the treatment pattern of RAS-driven tumors These inhibitors are expected to be the first FDA-approved drug to treat RAS-controlled tumors and will be used to treat refractive cancers driven by mutant RAS, such as PDAC, CRC, and LUAD Targeted mutation sourcin is the best way to treat RAS mutant tumors Despite these problems, the expected success of the first KRAS inhibitor is also encouraging, and further data is expected in the future, as well as early market listing of well-therapeutic KRAS inhibitors for the benefit of patients References: 1 Cancer Genome Atlas Network Comprehensive molecular molecular ization of human colon and rectal cancer Nature 487, 330-337 (2012) 2 Cancer Genome Atlas Network Dywer of the classification of cutanthye Cell 161, 1681-1696 (2015) 3 Cancer Genome Atlas Network Comprehensive molecular profiling of lung adenocarcinoma Nature 511, 543-550 (2014) 4 Cancer Genome Atlas Network Integrated gyda'r gyda'n sgourcynal adenocarcinoma Cancer Cell 32, 185-203.e13 (2017) 5 Cox, A D., Fesik, S W., Kimmelman, A C., Luo, J And der, C Drugging Theundruggable RAS: Mission Nat Rev Drug Discov 13, 828–851(2014) 6 Cancer Genome Atlas Network Comprehensive dywedd head and squamous cell carcinomas Nature 517, 576-582 (2015) 7 Robertson, A G et al Comprehensive molecular molecularization of muscle-bladder cancer Cell 171, 540-556 (2017) 8 Moore A R , Rosenberg S C , McCormick F , et al RAS-targeted therapies: is theundruggable drugged? (J Nature Reviews Drug, Discovery 2020 (13 Suppl.) 9 Bonfini, L., Karlovich, C A., Dasgupta, C and Banerjee, U The Son of Sevenless Geneproduct: a putactivator of Ras Science 255, 603-606 (1992) 10 Buday, L D J Epidermal growth factor regulates p21 ras through formation the formation of the a complex of the ball, Grb2 adapter, and sos nucleotide exchange factor Cell 73, 611-620 (1993) 11 Ebinu, J O et al Ras GRP, a Ras guanylotide released protein with calcium- and diacylglycellbinding motifs Science 280, 1082-1086 (1998) 12 Xu, G F et al The neurofibromatosis type 1 gene encodes a protein related to GAP Cell 62, 599-608 (1990) 13 Trahey, M M F A cytoplasmic protein cores cynos cynos cys normal N-ras p21 GTPase, butdoes not affect oncogenic mutants Science 238, 542-545 (1987).
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