IRS1 and IRS2 are the key protein effectors for transmitting insulin signals from the insulin-like growth factor receptor to the nucleus via the PI3K / AKT / mTOR pathway. IRS2 has been previously noted to be recurrently focally amplified in several anecdotal studies across multiple cancer types (colorectal cancer PMID: 23594372, cholangiocarcinoma PMID:26684807, glioblastoma PMID: 14655756, rhabdomyosarcoma PMID: 23578105), suggesting that this could be a "driver" alteration in a subset of cancer.. IRS2 amplifications have also been associated with sensitivity to the insulin receptor inhibitor BMS-754807 in colorectal cancer cell lines (PMID: 25527633). There is no direct evidence to connect IRS2 amplification status with sensitivity to any targeted therapy regimen in patients; however, an attractive hypothesis is that tumors harboring IRS2 amplifications could be sensitive to drugs targeting insulin signaling, PI3K, AKT, and mTOR. Drug sensitivity and exome sequencing data from colorectal patient derived tumor xenografts have associated IRS2 copy gains with sensitivity to anti-EGFR therapies (PMID: 26416732).