Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients

Abstract

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.

Figure 1.. G12C inhibitors and their mechanism of action

A) Chemical structures of G12C inhibitors with their initial publication date. The surface plot denotes the orientation of each inhibitor in the SIIP of mutant KRAS. The acrylamide warhead that engages the G12C residue is shown in green. The orientation of the histidine (H) 95 residue on KRAS is also shown. An interaction with this residue is thought to enhance the potency of inhibition. B) Superimposed structures of KRAS(G12C) bound to GDP alone, or in the presence of the indicated inhibitors. KRAS WT is included as a comparison. The surfaces in gray denote the area occupied by the inhibitors. Note the displacement of switch II in drug-bound structures. From 4LYF, 5F2E, 5V9L, 5V9U, 60IM, 6UT0, 4OBE and 4LDJ. C) Inactive state-selective KRAS(G12C) inhibition requires intact GTPase activity and occurs by preventing nucleotide-exchange to the active state. KRAS oncoproteins are insensitive to GAPs (dotted line, see text) and a relatively high intrinsic hydrolysis rate by KRAS(G12C) is thought to be sufficient for inhibition. The alternative possibility is that GTP hydrolysis by KRAS oncoproteins is aided by unidentified cellular factors (question mark). Space-filling models of GTP, GDP and G12Ci are respectively colored in red, blue and orange.

Figure 2.. Opportunities for combination therapy

A simplified schematic of KRAS signaling along with inhibitors targeting various intermediates reported to modulate KRAS(G12C) inhibition. Solid lines indicate a direct effect whereas dotted lines indicate indirect effects. Colors denote signaling intermediates along the same pathway.