What can be done if cancer turns resistance to KRAS inhibitors?

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. Cancer resistance is a major problem in cancer treatment. It is usual in clinical practice that tumor tissue becomes significantly smaller after targeted therapy, but soon deteriorates again. Can we develop a multi-mechanical combination therapy to eradicate the disease in order to solve the potential drug resistance problem before the tumor develops resistance to the research drug?

After screening 16,019 genes by shRNA screening, researchers at the Francis Crick Institute and the British Cancer Institute found that the KRAS-G12C inhibitor ARS-1620, and the insulin growth factor-1 receptor inhibitor linsitinib, were studied. The combination therapy with mTOR inhibitors can significantly reduce the tumor size of lung adenocarcinoma, and the effect is more durable. The 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, as well as multiple downstream pathways such as PI3K/AKT/mTOR, which control several key cellular activities, including proliferation, differentiation, survival, and angiogenesis. KRAS mutations occur in more than 90% of pancreatic cancers, 40% of colorectal cancers, and 16% of lung adenocarcinoma cases.

IGF1R is a membrane protein receptor with tyrosine kinase activity, 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.

Membrane receptor protein IGF-1R regulates downstream MAPK and PI3K/AKT/mTOR signaling pathways

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. The KRAS-G12C inhibitor ARS-1620 develop resistance and re-grow in a few weeks. The combination of KRAS-G12C inhibitor ARS-1620, IGF1R inhibitor linsitinib, and mTOR inhibitors can significantly 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.

Combination therapy under the study, KRAS-G12C inhibitor ARS-1620, IGF1R inhibitor linsitinib, and mTOR inhibitors has significant effect for lung cancer carrying KRAS-G12C mutation. Dr. Julian Downward, one of the authors, believes that the study provides a new approach 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 cancer when used as a single drug.”

References

  1. 1. Romero-Clavijo. et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aaw7999
  2. 2. Researchers Develop New Class of Lung Cancer Drugs. Retrieved Sep. 19, 2019, from https://www.biospace.com/article/new-class-of-drug-in-combination-shows-promise-for-lung-cancer/
  3. 3. Could a combo treatment boost KRAS inhibitors in lung cancer?. Retrieved Sep. 19, 2019, from https://www.fiercebiotech.com/research/improving-kras-inhibitors-lung-cancers-a-combo
  4. 4. Two Is Better Than One: Combining IGF1R and MEK Blockade as a Promising Novel Treatment Strategy Against KRAS-Mutant Lung Cancer. Retrieved Sep. 19, 2019, from https://cancerdiscovery.aacrjournals.org/content/3/5/491.figures-only