How to overcome drug resistance against KRAS inhibitors in cancer treatment?

Recently, KRAS and KRAS-G12C mutant inhibitors, which were previously considered to be "non-drugable" targets, have ignited a development boom. However, KRAS inhibitors are not a "magic bullet" for once and for all. Drug resistance is a major problem that frequently occurs in cancer treatment. In clinical practice, tumor tissue becomes significantly smaller after targeted therapy, but soon deteriorates again. Such scenes are commonly observed in real situations. Amgen's latest clinical trial results also indicate that some patients treated with the KRAS-G12C inhibitor AMG 510 continue to progress after remission. Can we develop a multi-mechanical combination therapy to eradicate the disease in order to solve the potential drug resistance problem before the tumor cells become resistant to the research drug?

After screening 16,019 genes by shRNA screening, researchers at the Francis Crick Institute and the Institute of Cancer Research (ICR) found that a combination therapy of the KRAS-G12C inhibitor ARS-1620, insulin growth factor-1 receptor (IGF1R) inhibitor linsitinib, and mTOR inhibitors, can greatly reduce the tumor size of lung adenocarcinoma, with more durable effect achieved. Both ARS-1620 and linsitinib are still at investigation stages. Relevant results of this trial were recently published in the journal Science Translational Medicine.

RAS family proteins are mainly divided into three categories: KRAS, HRAS, NRAS, and the KRAS gene mutation rate is more than 80%, which is one of the most common oncogenes. RAS protein regulation includes the MAPK signaling pathway (RAS-RAF-MEK-ERK) and multiple downstream pathways such as PI3K/AKT/mTOR, which control several key cellular activities including proliferation, differentiation, survival, and angiogenesis. According to statistics, KRAS mutations take place in more than 90% of pancreatic cancers, 40% of colorectal cancers, and 16% of lung adenocarcinoma cases.

As a membrane protein receptor, IGF1R has tyrosine kinase activity which is usually overexpressed in lung cancer. It is a key factor for malignant transformation upstream of the MARK and PI3K signaling pathways and is one of the leading causes of acquired resistance to EGFR inhibitors.

The researchers found that knocking out the MTOR gene made the cells significantly sensitive to KRAS and IGF1R inhibitors. While blocking the three signaling pathways, IGF1R, MAPK and PI3K/AKT/mTOR, cancer cells carrying KRAS mutations could not survive. ARS-1620, a KRAS-G12C inhibitor, was used alone to make tumor cells become drug resistant and re-grow in a few weeks. The combined therapy composed of KRAS-G12C inhibitor ARS-1620, IGF1R inhibitor linsitinib, and mTOR inhibitors can markedly reduce the size of mouse and human tumors, and the effect is significantly longer. This combination therapy has the potential to prevent or delay the resistance of KRAS-G12C inhibitors.

Dr. Julian Downward, one of the authors, believes that current research provides a new way to improve the efficacy of targeted mutant KRAS proteins. KRAS mutations often lead to greater invasiveness. "This provides a clear direction on how to better use KRAS-G12C inhibitors in the clinic and how to circumvent the possible evolution of drug resistance when used as a single drug."

Drug resistance

Once drug resistance occurs, the medication aimed at curing a disease or condition would be less effective than expected, which presents a biggest threat to the present therapeutics. Resistance to anticancer drugs results from a variety of factors, and individual genetic difference is just one of them. Clinically, drug resistance not only happens after drug therapy, but also happens prior to drug therapy.