Figure 1.

Strategies to target mutant KRAS cells. The lack of efficient therapies targeting mutant KRAS tumors represents an unmet clinical need. Several strategies have already been tested or are currently under development. Inhibitors of KRAS downstream effector molecules (e.g., RAF, MEK, PI3K) did not result in significant clinical benefit as standalone treatments, but their use in combination with receptor tyrosine kinase (RTK) inhibition has been shown to induce favorable antitumoral responses. The development of KRAS direct inhibitors represents a major breakthrough in the field, particularly of those targeting specific mutant forms, such as the G12C mutation, which are currently in clinical trials. Moreover, several other strategies under study aim to identify synthetic lethal interactors of KRAS, to impair KRAS post-translational modifications interfering with its subcellular localization, and to hamper the mechanisms used by mutant cells to obtain nutrients and energy.