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

Abstract

The non-receptor tyrosine kinase SRC promotes the progression of hematologic malignancies and numerous solid tumors. Several SRC kinase inhibitors have been approved for the treatment of hematologic malignancies. However, drug resistance to sole ATP pocket-targeted kinase inhibition, coupled with low potency for solid tumors and insufficient selectivity, has limited the clinical application of SRC kinase inhibitors. The non-catalytic functions of kinases have provided crucial mechanisms underlying kinase inhibitor resistance, thereby presenting new opportunities for discovery SRC-targeted strategies. In this study, we 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 prevents their proteasome-mediated degradation by the E3 ligase CHIP, ultimately inducing resistance to SRC kinase inhibitors. The peptide TS1-2, blocking SRC/TRIB3 interaction in non-catalytic regions, inhibits the tumor progression of pancreatic ductal adenocarcinoma (PDAC), 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 provides the insights 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 SRC/TRIB3 interaction as a potential non-catalytic target, and offers the candidate peptide TS1-2 as a potential combination strategy for overcoming SRC kinase inhibitor resistance. SignificanceThe scaffolding functions of SRC reduced the efficacy of SRC kinase inhibitors, and targeting SRC/TRIB3 non-catalytic functions synergizes the therapeutic effects of SRC kinase inhibitors in SRC-dependent solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/638389v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@17aa618org.highwire.dtl.DTLVardef@12e86eeorg.highwire.dtl.DTLVardef@19c8d82org.highwire.dtl.DTLVardef@10e6c46_HPS_FORMAT_FIGEXP M_FIG C_FIG SRC kinase inhibitors block myristoylation-dependent membrane location and catalytic phosphorylation of SRC. Phosphorylated SRC activates STAT1 and thereby represses TRIB3 transcription. Accumulated non-catalytic SRC promotes TRIB3, SPC24 transcription. Upregulated TIRB3 interacts with SRC to reduce CHIP-mediated ubiquitin-proteasomal degradation. The peptide TS1-2 disrupts TRIB3/SRC complex by targeting Non-kinase regions of SRC, consequently enhancing the therapeutic efficacy of SRC kinase inhibitors.