Targeting Non-Catalytic Sites of SRC Sensitizes the Efficacy of SRC Kinase Inhibitors in Solid Tumors

The non-catalytic functions of kinases have provided novel and crucial mechanisms underlying kinase inhibitor resistance, thereby presenting new opportunities for discovery of kinase-targeted drugs. Nevertheless, only a very limited modulators targeting non-catalytic functions have been reported. As the first discovered proto-oncogene, the non-receptor tyrosine kinase SRC promotes the progression of hematologic malignancies and numerous solid tumors via complex pathways. Several SRC kinase inhibitors were approved for the treatment of hematologic malignancies, yet not for solid tumors. The rapid development of resistance, attributed to the complexity of the signaling pathway, is a key factor restricting the application of SRC kinase inhibitors. The non-kinase function of SRC is one of the primary reasons, but the non-kinase function of SRC remains unclear. In this study, it was discovered that upon abrogation of phosphorylation by SRC kinase inhibitors, non-catalytic SRC promotes the transcription of the oncogenes TRIB3 and SPC24 transcription by binding to their promoter sequence. Simultaneously, it interacts with TRIB3 and mutually prevents the proteasome-mediated degradation by the E3 ligase CHIP, ultimately inducing resistance to SRC kinase inhibitors. The peptide TS1-2 inhibits the tumor progression of pancreatic ductal adenocarcinoma (PDAC), kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and breast invasive carcinoma (BRCA), and enhances the efficacy of SRC kinase inhibitors in solid tumors. This study elucidates the mechanism of non-catalytic functions of SRC, validates the tumor-promoting function and mechanism of nuclear accumulation of SRC/TRIB3 following SRC kinase inhibitor treatment, identifies a potential target SRC/TRIB3, and offers the candidate peptide TS1-2 as a new strategy for SRC kinase inhibitor resistance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/638389v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1af72d0org.highwire.dtl.DTLVardef@19aedf2org.highwire.dtl.DTLVardef@7bb800org.highwire.dtl.DTLVardef@6d0d60_HPS_FORMAT_FIGEXP M_FIG C_FIG