Disruption of the TNF-JNK-Axl-ERK axis at any level increases the sensitivity of GB to EGFR-TKIs.166 In CRC, CCR2 activates PI3K/AKT/GSK3β signaling and maintains β-linked protein stability, leading to regorafenib resistance.167 Ribonucleotide reductase subunit M2 (RRM2) competes with ubiquitin-protein ligase E3A (UBE3A) in RCC to bind to ANXA1, prevent ANXA1 degradation, and activate the AKT pathway, resulting in sunitinib resistance.168 In addition, Src, as an NRTK, also activates the PI3K/AKT pathway, leading to ALK-TKIs resistance in NSLCL.169. The gene discussed is UBE3A; the disease is colorectal carcinoma.