IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

In the current study, we delineate the molecular mechanisms of acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib and taselisib, in human papillomavirus positive head and neck cell lines. By comparing RNA sequencing of isiPI3K-sensitive tumor cells and their corresponding isiPI3K-acquired-resistant tumor cells, we found that overexpression of insulin growth factor 2 (IGF2) is associated with the resistance phenotype. We further demonstrated by gain and loss of function studies that IGF2 plays a causative role in limiting the sensitivity of human papillomavirus-positive head and neck cell lines. Moreover, we show that blocking IGF2 stimulation activity, using an inhibitor of the IGF1 receptor (IGF1R), enhances isiPI3K efficacy and displays a synergistic anti-tumor effect in vitro and superior anti-tumor activity ex vivo and in vivo. Overall design: we generated two acquired-resistant cell line models from UM-SCC47 and UT-SCC60A cells.UM-SCC47 and UT-SCC60A tumor cell lines were exposed to increasing concentrations of either GDC0032 or BYL719, respectively, for four to eight months, until resistance developed. We mapped the transcriptional landscape of isiPI3K-sensitive and isiPI3K-resistant cell lines by RNA sequencing (RNAseq). Specifically, we used the parental UM- SCC47 and UT-SCC60A and their corresponding acquired resistance models, UM- SCC47-Res2 and UT-SCC60A-Res2. Importantly, RNA extraction from the resistant cells was performed following 48 h of drug-free culture.