Mechanisms of acquired resistance to KRAS G12C inhibition in cancer

Dr Mark Awad - Dana-Farber Cancer Institute, Boston, USA

For our study in order to determine mechanisms of acquired resistance to KRAS G12C inhibitors we included patients that were treated on adagrasib or MRTX849 monotherapy in clinical trials. This included 23 patients with non-small cell lung cancer and seven patients with colorectal cancer. For patients included in our analysis we took a look at either repeat biopsies or circulating tumour DNA obtained at the time of disease progression on adagrasib and compared that to samples taken prior to adagrasib therapy initiation in the hopes of trying to identify genomic or histologic changes that developed over the course of treatment to determine the mechanisms of resistance to the drug.

What were the key results of the study?

In our study we identified several novel mechanisms of resistance to adagrasib. We found several mutations in what’s called the Switch-II binding pocket of KRAS. So we found novel alterations at KRAS amino acid position 95, so histidine 95 mutations, we found tyrosine 96 mutations, arginine 68 mutations as well as novel mutations affecting other portions of KRAS. We found that the KRAS G12C amino acid, that’s the cysteine residue that drugs like adagrasib and sotorasib covalently bind to, we found new mutations at KRAS G12, also at codon 13 and other KRAS alterations.

So we found a number of acquired mutations within KRAS, we call those on-target mutations and which also included acquired amplification of the G12C allele. Then we found several off-target mechanisms of resistance including mutations in genes like BRAF or NRAS or MEK, also called MAP2K1, as well as a number of acquired gene fusions in genes such as BRAF, RET, RAF1, ALK and others.

So by studying these samples we found many mechanisms of resistance. In some patients we found a single mechanism of resistance and in others we found multiple concurrent or simultaneous disease resistance mutations. We also identified a couple of cases that had histologic transformation from lung adenocarcinoma to lung squamous cell carcinoma and in those cases we did not find any acquired genomic alterations to explain the mechanism of resistance to the drug.

What impact might these results have on the future treatment and research of KRAS related cancers?

We think these findings have several implications for drug development. This is the first characterisation of how cancers can develop resistance to this class of drugs clinically and in patients. So we hope that this will inform subsequent trial design to either develop novel inhibitors to hopefully overcome some of these resistance mechanisms or to develop rational combination strategies that can be used up front in combination with KRAS G12C inhibitors to hopefully delay the emergence of resistance. Or once resistance emerges, to use those combinations ideally to overcome resistance. So our hope is that these findings will really inform subsequent clinical trial design and drug discovery.

Is there anything you would like to add?

I just wanted to thank… this was a real collaborative effort involving many different institutions as well as industry partners. I wanted to especially thank my close collaborator, Dr Andrew Aguirre at the Dana-Farber Cancer Institute. In his lab they did a very exhaustive mutagenesis screen of KRAS to try to identify additional mutations that could confer resistance to drugs like adagrasib and sotorasib. We also included a lot of preclinical data from his laboratory analysis and I really wanted to acknowledge his seminal contributions to this study.