HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function

Abstract

Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS–GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target.

Semi-Synthetic Dihydrotestosterone Derivatives Modulate Inherent Multidrug Resistance and Sensitize Colon Cancer Cells to Chemotherapy

“…Colo 320 cells have been shown to exhibit drug resistance, overexpress several ABC transporters, carry a mutation in the tumor suppressor protein APC, and the proto-oncogene c-myc is amplified in these cells. It is a model system for inherent MDR [ 10 , 32 , 33 , 34 , 35 , 36 ], while drug-sensitive Colo 205 cells were used as a control [ 34 , 35 , 37 , 38 , 39 , 40 ]. Thus, the primary aim of this present work was to examine the sensitizing potential of semi-synthetic androstane derivatives on inherently multidrug-resistant Colo 320 colon adenocarcinoma cells.…”