The question of whether the more limited activity of KRASG12C inhibitors in CRC compared to NSCLC is related to the earlier emergence of multiple acquired resistance mechanisms or to the existence of adaptive signaling pathways will need intensified research and supports the basis for ongoing clinical trials of adagrasib (NCT04330664) or sotorasib (NCT04185883) in combination with inhibitors of RTKs or SHP2. Here, PTPN11 is linked to colorectal carcinoma.