Table 1.

Factors contributing to the disease heterogeneity of KRAS-mutant non-small-cell lung cancer (sources).

▪KRAS mutational isoforms differ in their biochemical properties to hydrolyze GTP and to activate downstream signaling pathways. This determines their biological behavior and affects therapeutic vulnerabilities [31,32,33]. ▪Wild-type KRAS protein dimerizes with mutant KRAS. This dimerization affects the transforming potential of mutant KRAS and impacts therapeutic interventions (e.g., MEK inhibition) [34]. ▪Cancer cells and tumors have variable “RAS dependencies” [35,36]. ▪Co-occurring genetic events like mutations in TP53, STK11 and KEAP1, among other genes, define clinically relevant subtypes [39,40,41,42,43]. ▪The smoking-associated etiology is the basis of a high mutational burden [69,70,71,72]. ▪The tumor immune microenvironment ranges from T-cell-deprived (“cold”) to T-cell-inflamed (“hot”) [41,73,74,75].