Direct GDP-KRAS^G12C inhibitors and mechanisms of resistance: the tip of the iceberg

Abstract

Kirsten rat sarcoma viral oncogene homolog mutations are observed in 25% of lung adenocarcinoma and 40% of these are G12C mutations. Historically, no approved targeted agents were available for patients with any KRAS mutation, and response rates to standard-of-care therapies were suboptimal. Newly developed inhibitors directed toward KRASG12C have been successful in clinical trials with overall response rates ranging between 32% and 46%, and two FDA approvals were granted in May 2021 and December 2022 as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy. With the rapid development of this novel class of inhibitors, it is important to discern the different types of tumor resistance that may arise and how each can differently contribute to tumor growth and survival. G12C inhibitor resistance is under investigation and combinations of therapies with G12C inhibitors have been proposed. Much of this insight is gleaned from preclinical investigations, as our knowledge of clinical resistance is in its infancy. In this review, we summarize the preclinical development of KRASG12C inhibitors, their clinical evaluations, different types of resistance mechanisms to these compounds, and ways of overcoming them. Finally, we underscore the importance of basic and translational investigations of these molecules in a landscape where their clinical evaluations garner the most attention, and we set the stage for what is to come.

Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib

“…Importantly, our work goes further than previous proteomics screens as, for the first time, we characterised the changes caused by Sotorasib in the KRAS WT and KRASG12C interactomes. This KRASG12C-specific inhibitor is already approved for the treatment of lung cancer but resistance to treatment develops quickly [ 13 ]. Additionally, unspecific effects have been reported and it has also been shown to have effects in cell lines regardless of KRAS mutation status [ 70 , 71 ].…”

“…Additionally, unspecific effects have been reported and it has also been shown to have effects in cell lines regardless of KRAS mutation status [ 70 , 71 ]. Reports also indicate that several patients develop severe side effects which indicate that at therapeutic concentration the drug has a systemic impact affecting cells that do not express KRASG12C [ 13 ]. One important consideration is that we used very high concentrations of Sotorasib in our study and some of the changes in KRASG12C and KRAS WT interactomes that we see in our screen might not occur at nM concentrations of Sotorasib.…”

“…Additionally, we consistently observed a cell-type-specific increase in activating AKT phosphorylation in MEFs and HKe-3, but not HEK293. Activation of AKT upon Sotorasib treatment has been associated with resistance to this treatment in patients and is reported in several cell lines [ 13 , 57 , 71 , 72 ]. Importantly, our AP-MS approach identified clear changes in the interactomes of both KRAS WT and KRASG12C that potentially can explain the Sotorasib-induced AKT activation.…”

“…The development of a series of covalent inhibitors specific for KRASG12C and the FDA approval of Sotorasib (AMG510) and Adagrasib demonstrate that we can develop effective RAS inhibitors, at least for some of the most common mutants [ 12 ]. Unfortunately, while the initial response rates to Sotorasib and Adagrasib are promising, ranging from 32% to 46%, respectively, in non-small cell lung cancer (NSCLC), resistance inevitably develops in these patients [ 13 ]. These drugs can also lead to severe side effects in the patients and more information is necessary to fully characterise their mechanism of action [ 14 ].…”

Resistance to KRAS inhibition in advanced non-small cell lung cancer

“…One approach is to target upstream effector proteins of the KRAS protein itself. For instance, the phosphatase son of sevenless homolog 1 (SOS1) is a RAS guanine nucleotide exchange factor (RasGEF), which is activated by SHP2 promoting RAS activation through GTP binding ( Figure 1 ) ( 112 ). The combination of a novel SOS1 inhibitor (BI-3406) and trametinib exhibited potent activity against Y96D and Y96S ( 113 ).…”