Targeting Receptor Kinases in Colorectal Cancer

Abstract

Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment.

Control of Tyrosine Kinase Signalling by Small Adaptors in Colorectal Cancer

“…In CRC, RTKs of the EGFR, VEGFR, ephrin (EPHs), discoidin domain receptor (DDR) and MET hepatocyte growth factor receptor families, and CTKs of the SRC, focal adhesion kinase (FAK) and Janus kinase (JAK) families have been linked to cancer progression; however, the genes encoding these TKs are not frequently mutated or amplified in these tumours [13,14,15]. Unlike CML, the level of TK expression or activity is not a good predictor of therapeutic response in CRC.…”

MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

“…Its usage, in combination with cetuximab, was reported to inhibit cell proliferation and CRC xenografts [ 120 ]. Brigatinib, which inhibits IGF-1R [ 121 ], and Amiodarone, a Thyroid Hormone Receptor antagonist [ 122 ], were studied with encouraging results. Significant outcomes have also been obtained with natural products in resistant CRC cells.…”

Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy

“…On the other hand, under the pressure of the immune system and oncologic treatments, the activation of cellular mechanisms leading to apoptosis inhibition and cell survival represents a selective advantage for tumor cells over other cells [41]. Over time, this phenomenon, along with the typical genomic instability of tumor cells, increases the probability that these cells acquire new mutations affecting additional kinases down-stream receptor kinases.…”

“…On the other hand, the Enzyme List created by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology includes human protein kinases into the Class 2.7-Transferring phosphorus-containing groups [40] and classifies them into 13 subcategories, being 2.7.10 Tyrosine Kinases and 2.7.11. Serine/Threonine Kinases groups the two major representatives regarding their role as key elements in the regulation on most cellular activities [41]. In 2002 of The Protein Kinase Complement of the Human Genome also proposed the classification of human kinases into these 10 main groups regarding catalytic domain sequence comparisons: AGC (A, G and C protein kinases), CAMK (Ca2+/CAM-dependent protein kinases), CK1 (casein kinase 1), CMGC (CDK, cyclin-dependent kinases; MAPK, mitogen-activated protein kinases; GSK3, glycose synthase kinase-3; CLK, cdc2-like kinases), RGC (receptor guanylate cyclase), STE (homologues of yeast sterile 7, 11, 20 kinases), TKs (tyrosine kinases), TKL (tyrosine kinase-like protein kinases), Other Kinases group and the Atypical group [42].…”