Disrupting the protein signaling activity of MAPK pathway as target for metastatic colorectal cancer therapy

Abstract

Despite recent advances including the use colonoscopy for early detection of colorectal cancer (CRC), the 2019 incidence and death rates projection for the disease in the U S were still alarming, as they stood at 145,600 and 51,020, respectively. Patients with the metastatic colorectal cancer (mCRC) subtype remain without hope as they do not respond or quickly develop resistance to the current available therapeutics. Over 50% of patients with CRC harbor constitutively active K‐Ras and 10% with B‐Raf mutations. Men of African American descent are more likely to be diagnosed with mCRC and will equally die of it compare to other races. Also, the most aggressive and deadly subtype with constitutively active mutant B‐Raf is commonly diagnosed in women and patients of more advanced age. Therefore, investigating novel targeted therapy to inhibit and disrupt the activities of the driver mCRC remains a matter of urgency. Recent tests for biological activities of novel agents, polyisoprenylated cysteinyl amide inhibitor (PCAIs) designed and synthesized to target the hyperactivity of aberrant monomeric G‐Proteins such as Ras and Rho protein family show promising results for continued development as a drug molecule. We hypothesized that the PCAIs would target and suppress the hyperactivity of aberrant Mutant K‐Ras and/or B‐Raf function that drive the aggressive mCRC subtype. To test this hypothesis, we screened for the potency of PCAIs on inhibiting the cell viability of 2D and 3D cultures of different CRC cells including Caco‐2, HCT116 and HT‐ 29 cells. We also evaluated the mechanism by which they induce cancer cell death. Our results indicate that the PCAIs NSL‐BA‐040 and NSL‐BA‐055 inhibited 2D Caco‐2 cells cultured at very low concentrations of 3.8 and 1.4, respectively, and 2.2 and 1.5 μM, respectively for HCT116 cells. For the 3D cultures, NSL‐BA‐040 and NSL‐BA‐055 induced cell death of spheroids at EC50 of 20 and 5.5 μM, respectively. NSL‐BA‐055 induced cell death by apoptosis, blocks spheroid growth and shrinks their volumes. The effects of the PCAIs on HT‐29 2D and 3D cell cultures were even more dramatic. The PCAIs tested here demonstrate significant potency on CRC cells while sparing HEK293 cells. Since these PCAIs demonstrate a strong drug‐like property at this early stage of their development, they would be further tested, characterized and hopefully developed as drug for CRC therapy, targeting the drivers of the metastatic subtype.Support or Funding Information“Research reported in this publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health”.