The end of KRAS, and other, cancers? A new way forward

Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells

“…For our investigations we selected SW620 cells derived from a human metastatic colorectal cancer and SW480 cells from the primary isogenic parent tumour, both carrying a Kras-G12V mutation and biallelic mutations in TP53 (R273H and P309S) and both unresponsive to current therapeutic attacks but responsive to βGBP treatment that arrests their proliferation and forces them into programmed cell death. 5,11 In our experiments we have used the lowest therapeutically effective dose of human recombinant βGBP (2 nM) that induces growth arrest and apoptosis, 11 a dose about fifty-fold lower than that required (~100 nM) for βGBP to act as a down-regulatory cytokine during the silencing phase of a T cell immune response. 6 βGBP induces cell arrest, ER stress, autophagy and apoptotic death First, we looked for growth arrest, time related expression of apoptotic parameters and cellular death, along with evidence of ER stress and autophagy, obligatory determinant factors for ICD induction.…”

“…Unlike drugs and other foreign agents, βGBP, a natural immunomodulator, operates through biological mechanisms and functions that proceed according to a program. They initiate with high affinity βGBP receptor binding followed by PI3K downregulation and signalling hence, 5,7,[10][11][12] events that result in cancer cell death through a graded process that allows procedures that lead to ICD to take place.…”

“…To test this hypothesis, we have adopted a strategy centred on the use of a molecular component of the immune network with a candidate role in cancer immunosurveillance. 5 We have utilised the15kD β-galactoside-binding protein (βGBP) a molecule primarily produced by activated CD8+ T cells, by CD8+ memory cells and by activated CD4+ T cells, 6 which has cytostatic properties and selective anti-tumour properties. [7][8][9][10][11] While arrested normal cells preserve the ability to resume proliferation after βGBP treatment, 7 arrested cancer cells regardless of mutational load undergo apoptotic death.…”

“…[7][8][9][10][11] While arrested normal cells preserve the ability to resume proliferation after βGBP treatment, 7 arrested cancer cells regardless of mutational load undergo apoptotic death. 5,[8][9][10][11] βGBP operates through mechanisms that involve high affinity receptor binding (Kd~1.5 × 10 −10 mol/L 7 ) and molecular interactions leading to functional inhibition of the p110 class1A and class 1B PI3K catalytic subunits. 12 Consequent downregulation of PI3K activity has two major outcomes which are reversible in normal cells but not in cancer cells: suppression of Ras-GTP loading leading to block of ERK activation 12 and negation of akt gene expression leading to loss of Akt 10 function, conditions that either by blocking the ability of cancer cells to proliferate or by impairing their ability to survive can block oncogenicity.…”

“…Therapeutically human βGBP has been proven to strongly reduce human Kras-mut/TP53-mut colorectal cancer xenograft growth as a single agent 11 and, as a single agent, to drive to apoptotic death a variety of cancer cells from solid tumours, including cells sourced from colon, pancreas, prostate and breast which bear Kras mutations and tumour suppressor deficiency. 5 Here we have investigated key canonical events which are fundamental to ICD induction. We have focused on endoplasmic reticulum (ER) stress, autophagy, [13][14][15] calreticulin (CRT) transfer from the lumen of the ER to the surface of the cancer cell and the release of ATP by the dying cancer cell [16][17][18][19] and, consequent to these events, we have assessed dendritic cell (DC) activation, and found that the stated requirements for ICD induction were met.…”