Understand KRAS and the Quest for Anti-Cancer Drugs

Abstract

The KRAS oncogene is mutated in approximately ~30% of human cancers, and the targeting of KRAS has long been highlighted in many studies. Nevertheless, attempts to target KRAS directly have been ineffective. This review provides an overview of the structure of KRAS and its characteristic signaling pathways. Additionally, we examine the problems associated with currently available KRAS inhibitors and discuss promising avenues for drug development.

Keywords: KRAS; cancer; inhibitors; signaling pathway.

Figure 1

Domain structures and the three-dimensional structure. (A) Domain structure of full-length KRAS. (B) Ribbon representation of the monomeric crystal structure of KRAS (PDB ID: 7C40) using the program PyMOL. The Mg²⁺ ion is indicated by a gray circle and guanosine diphosphate (GDP) by a yellow rod. The MgGDP molecule is color-coded as follows: C yellow, O red, N blue, P purple, and Mg²⁺ gray.

Figure 1

Domain structures and the three-dimensional structure. (A) Domain structure of full-length KRAS. (B) Ribbon representation of the monomeric crystal structure of KRAS (PDB ID: 7C40) using the program PyMOL. The Mg²⁺ ion is indicated by a gray circle and guanosine diphosphate (GDP) by a yellow rod. The MgGDP molecule is color-coded as follows: C yellow, O red, N blue, P purple, and Mg²⁺ gray.

Figure 2

Characteristic KRAS signaling pathways. In the active guanosine triphosphate (GTP)-bound state, KRAS interacts with several families of effector proteins and stimulates their catalytic activities. Raf protein kinases activate mitogen-activated protein kinase kinases 1 and 2 (MEK1 and MEK2), which leads to extracellular-signal-regulated kinase (ERK)1/2 activation. Phosphoinositide 3-kinases (PI3Ks) generate second-messenger lipids and activate numerous target proteins, including the survival signaling kinase AkT. KRAS binding activates Ral-specific guanine nucleotide exchange factors (RalGEFs) by directing them to their Ral GTPase substrates in the plasma membrane. KRAS is indicated by a green frame shape, Raf/MEPK/ERK by an orange, PI3K/Ark/PDK1/mTOR by a sky blue, Ral by a brown, and GDP/GTP by a yellow circle. The nucleotide exchange factors (GEF) is indicated by a magenta, RALGEF and GTPase activating proteins (RALGAP)/RalGEF by a red, and ZONAB Sec5/Exo84/Filamin/RalBP1/PLD1 by a dark sea green rectangle.