Molecular and morphological profiling beyond organ characteristics (trans-organ analyses)

RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS G12C-specific inhibitors show clinical activity in patients with cancer, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. We uncovered the requirement of a silent mutation in KRAS G60G for a functional KRAS Q61K oncogenic protein. The team further reveal that the region around RAS Q61　has splicing vulnerabilities and proposed a novel RAS Q61 cancer treatment strategy using mutant-selective antisense oligos. In addition, using CRISPR genome editing techniques employed in this study, we created cell line models with fusion genes as mechanisms of drug resistance in EGFR mutant lung cancer. These models identified effective combination therapies for overcoming fusion genes. We also revealed further various resistance mechanisms against combination therapies.

Figure 5 Silent mutations in RAS Q61 cancers and a novel mutant-selective treatment strategy

In addition, we reported that the tumor cell content in cancer gene panel tests is easily overestimated, but that training can make this assessment more uniform (Fig. 6).

Figure 6 Effects of Training on Improving Tumor Cell Content Assessment in Cancer Gene Panel Tests