Oncogenic KRAS: Signaling and Drug Resistance

Abstract

RAS proteins play a role in many physiological signals transduction processes, including cell growth, division, and survival. The Ras protein has amino acids 188-189 and functions as GTPase. These proteins are switch molecules that cycle between inactive GDP-bound and active GTP-bound by guanine nucleotide exchange factors (GEFs). KRAS is one of the Ras superfamily isoforms (N-RAS, H-RAS, and K-RAS) that frequently mutate in cancer. The mutation of KRAS is essentially performing the transformation in humans. Since most RAS proteins belong to GTPase, mutated and GTP-bound active RAS is found in many cancers. Despite KRAS being an important molecule in mostly human cancer, including pancreatic and breast, numerous efforts in years past have persisted in cancer therapy targeting KRAS mutant. This review summarizes the biological characteristics of these proteins and the recent progress in the exploration of KRAS-targeted anticancer, leading to new insight.

Keywords: GTPase; KRAS; drug resistance; inhibitor; mutant; signaling.

Figure 1

The branched tree of RAS superfamily. RAS superfamily comprises 150 human members and is divided into five different major branches. The Ras sarcoma (Ras) family comprises 36 members and has been the subject of intense research. The Ras homologous (Rho) family comprises 20 members, RhoA, Rac1, and Cdc42 being the best studied. The Ras-like proteins in brain (Rab), the largest branches of the superfamily, comprise 61 members. The ADP-ribosylation factor (Arf) family comprises 27 members; Rab and Arf families have similar functions. The Ras-like nuclear (Ran) family presents only one member [1,8].

Figure 2

RAS cycles between ‘inactive’ state bound to GDP and ‘active’ state bound to GTP. RAS acts as a guanosine diphosphate (GDP)-inactive molecular switch in resting cells and becomes activated in response to extracellular receptors by binding guanosine triphosphate (GTP), as catalyzed by the guanine nucleotide exchange factor (GEF). The GTPase-activating protein (GAP) stops the Ras signaling by switching Ras into an inactive GDP-bound signaling state. PDB IDs: 7C40 (RAS-GDP), 6Q21 (RAS-GTP), 1WQ1 (GAP-RAS), and 4G0N (GEF-RAS).

Figure 3

Structure analysis of KRAS. Schematic representation of the full-length KRAS isoform domain. KRAS consists of G domain (residue 1–166) and hypervariable region (HVR, residue 167–188/189). G domain is divided into effector lobe (residue 1–86) and allosteric lobe (residue 87–166). In addition, effector lobe consists of P-loop-phosphate binding loops (residue 10–16), Switch I (residue 30–38), and Switch II (residue 59–76).

Figure 4

Signaling pathway of KRAS protein. Activation of RAS occurs when epidermal growth factor (EGF) binds to tyrosine kinases receptor such as epidermal growth factor receptor (EGFR). KRAS protein is activated by binding to GTP, transducing the cytoplasmic signal, which activates the RAL, RAF-MEK-ERK, and PI3K-AKT cascade. These cascades regulate cell growth, division, and differentiation.