The KRAS oncoprotein is a GTPase and an essential mediator of intracellular signaling pathways. They are involved in tumor cell growth and survival. Somatic, activating mutations in KRAS are a hallmark of cancer. Furthermore, they prevent the association of GTPase-activating proteins, thus stabilizing effector binding and enhancing KRAS signaling. KRAS G12C is present in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid tumors. It is present in the inactive GDP-bound form of KRAS. There are some inhibitors of several MAPK pathway proteins for a subset of tumor types, but has no selective for KRAS-mutant tumors. Moreover, several MAPK-pathway-targeting therapies are contra-indicated for the treatment of KRAS-mutant tumors owing to a lack of clinical efficacy. Sotorasib is a first-in-class, orally bioavailable, and selective KRAS G12C covalent inhibitor. It is the first KRAS G12C inhibitor in clinical development.

Sotorasib is a first-in-class and selective KRAS G12C covalent inhibitor and the first one in clinical development.

Sotorasib irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Moreover, it leads to the regression of KRAS G12C tumors. In two KRAS G12C cell lines, NCI-H358 and MIA PaCa-2, Sotorasib almost completely inhibited p-ERK (IC50≈0.03 μM) after a 2-hour treatment. Sotorasib also potently impaired cellular viability in both NCI-H358 and MIA PaCa-2 (IC50≈0.006 μM and 0.009 μM respectively. In cell-viability assays, Sotorasib impaired the growth of all KRAS G12C cell lines, except SW1573, with IC50 values ranging from 0.004 μM to 0.032 μM.

In three KRAS G12C tumor models, Sotorasib inhibited p-ERK in a dose-dependent manner 2 h after treatment. Moreover, the maximal inhibition doses range from 30-100 mg/kg. In mice with xenografts of human tumor cells, Sotorasib significantly inhibited the growth of MIA PaCa-2 T2 and NCI-H358 tumors at all doses (30-100 mg/kg). Moreover, higher doses lead to the regression of tumors.

Sotorasib, a first-in-class oral KRAS G12C inhibitor. Preclinically, Sotorasib selectively targeted KRAS G12C tumors. Thus, Sotorasib might be an effective anti-tumor agent even in settings in which KRAS G12C expression is heterogenous.


Canon J, et al.  Nature. 2019 Nov;575(7781):217-223.