Currently, sotorasib and adagrasib have been approved by the US FDA to treat patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation. However, their efficacy is somewhat limited compared to that of other targeted therapies owing to intrinsic resistance or early acquisition...
KRAS G12C is another significant mutation found in 13% of lung cancers and 3% of colorectal cancer [7], [8]. This mutation, identified as an oncogenic driver of tumorigenesis, has been considered druggable, as the presence of the substituted cysteine provides a target for drug binding [5]...
Screening of small molecules that covalently bind to KRASG12C led to the discovery of multiple highly potent and selective covalent inhibitors for the treatment of various solid tumors, for example, Sotorasib (AMG510, 6) and Adagrasib (MRTX849, 7) [217–221]. Through a cysteine- reactive...
demonstrated that the prognosis of patients having surgery for early-stage NS-NSCLC showing a KRAS G12C mutation had more recurrence than in cases of other KRAS mutation subtypes or KRAS wild-type tumors, thus opening the door in the future for potential adjuvant therapy targeting KRAS G12C [...
KRAS tumor mutations were detected in about 35% of patients; about 65% of patients had KRAS wild type tumors. KRAS mutation in colon ca blocks Cetuximab ELI-002 is an "AMP KRAS vaccine" containing seven Amphiphile mKRAS peptides and a proprietary Amphiphile adjuvant, administered subcutaneously....
*19 c.1184delG NM_004456.4 22.4% 4819 PTCH1 p.S1203Afs*52 c.3606delC NM_000264.3 28.6% 3713 ATM p.R1973Efs*17 c.5917delA NM_000051.3 11.2% 1436 KRAS p.G13D c.38G>A NM_033360.2 14.0% 2526 KRAS p.G12D c.35G>A NM_033360.2 5.3% 2533 BRCA2 p.K1691Nfs*15 c.5073delA NM...
CD90+ CAFs promotes tumor cell inva- sion by enhancing tumor cell–endothelial cell attachment in a KrasG12D-driven LUAC (KrasLA1) mouse model [159]. In hepatocellular carcinoma (HCC), a significant number of CAFs highly express CD90, which correlates with angiogenesis markers (CD105, ...
[114] conducted scRNA-seq on 34 patient-derived xenograft (PDX) cells isolated from a xenograft tumor of a lung adenocarcinoma (LUAD) patient, and identified a tumor cell subpopulation related to anti-cancer drug resistance that expressed KRASG12D through gene expression and mutation profiling. ...
mutation [212,213]. An additional important advantage of targeted covalent inhibitors is the inhibition of targets with shallow, undruggable binding sites. For example, KRAS, long viewed as “undruggable,” has now been targeted in tumors including NSCLC, pancreatic and colorectal cancer bearing the...
The three tissue-specific isoforms—HRAS, KRAS, and NRAS—of the RAS gene family encode small GTPase proteins bound to the cytoplasmic membrane. Among them, NRAS is the most commonly mutated gene in CMs (189/686, 27.6%), whereas the involvement of the other two isoforms is minimal (HRAS,...