KRAS G61

We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network.

The hit found by the combination of structure-based pharmacophore generation, pharmacophore- based virtual screening, and molecular docking showed interaction with key amino acids in the hydrophobic pocket of PDEδ, leading to the discovery of a novel scaffold as a potential inhibitor of PDEδ.

Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E (equivalent of V600E in humans) in urothelial carcinoma. Our findings better position canines as a translational model of human cancer to investigate a wide spectrum of targeted therapies.

Patients with AOCRC harbored more somatic variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases carried unique genomic alterations that varied across the TMB and microsatellite subpopulations. BRAF V600E and RNF43 truncating mutations were more frequent in AOCRC.

Patients with LOCRC were more likely to have pathogenic gene variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases harbored unique genomic alterations that varied between the TMB-low/MSS, TMB-H/MSI-H, and TMB-H/MSS subpopulations.

As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization.

Our study revealed the different KRAS muts harboring different genomic profiling for Chinese NSCLC patients. These findings could be useful to provide a roadmap for precision medicine development of NSCLC in China.

We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.