AACR 2020: Targeting the KRAS Pathway – Old Protein, New Approaches
By T. Chakraborty, Ph.D.
The proto-oncogene protein p21 (RAS) is the most frequently mutated protein in cancers and is present in 90% of pancreatic cancer, 35% lung cancer, and 45% colon cancer patients. In humans, three different RAS proteins are present; KRAS, NRAS, and HRAS. KRAS is the most prevalent form of RAS mutation among all three cancers . KRAS exists in two different forms, a GDP bound inactive stage, and a GTP bound active state. Mutations generally lead to irreversible binding of KRAS to GTP, thereby activating the downstream signaling through Mitogen-activated protein kinase (MAPK) pathway and cell survival. KRAS mutations have been known for multiple decades to be a cause of cancer, but not much progress has been made to-date to target this protein for cancer treatments .
Kinase Screen Identifies Specific Signaling Associated with Different KRAS Mutations in Colorectal Cancer.
One of the unique characteristics of KRAS mutations in colorectal cancer is the variety of alleles observed. The most prevalent are G12D, G12V, G12C, G13D, Q61L, and G12R. Each of these alleles may affect different cellular signaling mechanisms making KRAS a difficult drug target. For example, G12D is sensitized to epidermal growth factor receptor-targeted therapy, while the other mutations are not suggesting that each mutated allele may have a specific response to therapies targeting KRAS. Dr. Jonathan Chernoff’s lab at Drexel University, created a CRISPR based novel system to model various KRAS mutations in a mouse epithelial cell line. Using this novel cell line, Dr. Chernoff’s lab, performed a kinase inhibitor screen to identify specific kinases which are associated with specific KRAS alleles. It was demonstrated that the G12V allele of KRAS was sensitized to Cyclin D kinase 4 inhibitors, while G12D mutation was not sensitized. This indicated the specific role of Cdk4 in downstream signaling of G12V mutation and not G12D mutation. This is an important breakthrough as this novel cellular system can be used to model different KRAS mutations associated with the disease. Furthermore, this approach can help in small molecule screens and is be a step towards precision medicine in KRAS therapy .
Novel SOS1 Inhibitor in Combination Therapy: A Probable Allele Independent KRAS-Targeted Therapy
Various clinical trials targeting the MAPK pathway to reduce hyperactivation of KRAS have failed due to the negative feedback loop, which controls KRAS activity. Guanosine exchange factor, SOS1, is a key component of that feedback loop that mediates the attachment of KRAS to GTP. Dr. Marco Hofmann and colleagues from Boehringer Ingelheim RCV GmbH and Co, Austria, in collaboration with MD Anderson cancer center, proposed a combination therapy using the SOS1 inhibitors, BI 1701963 and BI-3406 as potential treatments for KRAS dependent cancer. BI-3406 is a non-clinical compound and was used for proof of principle studies, whereas BI 1701963 is approved for clinical use and has similar efficacy and better safety profile. Both these drugs are orally available and bind to the catalytic domain of SOS1, thereby reducing its interaction with KRAS-GDP.
3D proliferation assay using a cancer line showed that both these drugs sensitized the cells irrespective of the KRAS mutation present other than Q61H, which was resistant to the SOS-1 inhibition. Further, both these drug treatments enhanced the level of KRAS-GDP, the inactive form of KRAS, and decreased MAPK target genes. Finally, Dr. Hofmann demonstrated that combination therapy of BI 1701963 with Mitogen-activated protein kinase (MEK) inhibitor trametinib and with irinotecan, a well-known chemotherapy agent showed efficacy in mouse KRAS tumor model. Furthermore, BI 1701963 treatment with trametinib combination reduced biomarkers as well as MAPK target proteins and caused apoptosis in a xenograft model. Dr. Hofmann concluded that BI 1701963 is currently in Phase I clinical trial as a monotherapy or with combination therapy for safety and efficacy in a multi-center study. If successful, this will be a huge milestone for KRAS-targeted therapy .
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