Post-Treatment Resistance to KRAS-Targeted Therapy Triggers a Spectrum of Diverse Mutations, According to Nature Study

If we talk about which targeted therapy drug against a specific site has been the most exciting in recent years, I would vote without hesitation for the small-molecule targeted drug combating the "strongest cancer gene" – KRAS.

After all, pancreatic cancer, colorectal cancer, and non-small cell lung cancer (NSCLC), which have relatively high frequencies of KRAS gene mutations, are all formidable opponents, and many patients previously had no access to precise treatment drugs. Sotorasib and adagrasib, the pioneers among targeted drugs that inhibit the KRAS G12C mutation, have already reported promising preliminary efficacy data.

However, in early studies treating NSCLC patients, the objective response rates (ORR) for sotorasib/adagrasib were 35-45%, and the median duration of response (DoR) with sotorasib treatment was less than one year, indicating that many patients experienced primary or secondary resistance, limiting the therapeutic benefit.

The next step in the development of targeted therapy is to solve the puzzle of drug resistance.

Recently, a team from Memorial Sloan Kettering Cancer Center (MSKCC) and a team from Amgen, the developer of sotorasib, published a new study in Nature, analyzing gene mutations associated with sotorasib resistance. This provides crucial reference information for subsequent clinical medication and treatment strategies [3].

This analysis included a total of 43 patients from two Phase I/II clinical studies of sotorasib, including 36 with NSCLC, 3 with colorectal cancer, and 4 with other solid tumors such as pancreatic cancer. At the time of manuscript submission, 4 patients were still continuing treatment.

Eight patients had an excellent response to sotorasib treatment (defined as complete or partial remission lasting more than 12 months). Prior to treatment, these patientsTumorThe load is relatively low, and the frequency of the KRAS G12C allele mutation detected in the serum is also low. However, whether these two indicators can predict efficacy remains to be analyzed in large samples.

Researchers performed next-generation sequencing (NGS) on tissue or liquid biopsy samples before and after treatment, revealing genetic alterations in 27 patients post-treatment, including secondary variations in the RAS gene family such as KRAS G12D/V/F or V8L site mutations, KRAS copy number amplification, NRAS mutations, as well as BRAF mutations and EGFR amplification/point mutations.

The vast majority of secondary mutations in the RAS gene family or other gene mutations occur at relatively low frequencies. However, preclinical studies using patient-derived tumor xenograft (PDX) models have shown that some of these mutations do lead to drug resistance.TumorResistance to KRAS-targeted drugs is similarly "fragmented."

Take, for example, the RAS family secondary mutations such as KRAS G12V and NRAS Q61K, which may mediate resistance. Researchers analyzed 1,432 cases of KRAS G12C in the MSKCC sample database.TumorSamples revealed that the incidence of these mutations was previously only 3%, but increased to 16-22% in patients treated with sotorasib.

Preclinical studies on PDX models show that these genetic variations do not affect the binding of sotorasib to the therapeutic target KRAS G12C, but they can "bypass" and activate downstream pathways, thereby partially offsetting the efficacy of sotorasib in inhibiting cancer cell proliferation, ultimately leading to treatment resistance.

Of course, new genetic mutations mean new treatment possibilities. Researchers analyzed drug-resistant cells using CRISPR-Cas9 and found that the primarily activated downstream pathway was the ERK signaling pathway. Therefore, adding a MEK inhibitor, trametinib, to sotorasib or using an investigational new drug targeting the ERK/RAF dimer has shown promising results.

However, the researchers also specifically pointed out that due to the fragmented nature of sotorasib resistance mechanisms, it is not realistic to find a "one-size-fits-all" solution that破解s resistance for all patients. For example, the sotorasib + trametinib regimen can only target patients with secondary gene mutations in the RAS family.

Therefore, personalized and precise interventions based on possible resistance mechanisms discovered through NGS will be the main approach to addressing KRAS G12C inhibitor resistance in the near future. It is also hoped that drugs for some sites without available treatments will soon become accessible.BioValleyBioon.com）