Abstract

Sunitinib, an oral tyrosine kinase inhibitor used in advanced renal cell carcinoma (RCC), exhibits significant efficacy but faces resistance in 30% of patients. Yet, the molecular mechanisms underlying this therapy resistance remain elusive. Here, we show that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. The activation of the GCN2-ATF4 stress response pathway is identified as the mechanistic link between sunitinib treatment and elevated serine production. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhances the sensitivity of resistant cells to sunitinib. The study underscores the role of serine biosynthesis in nucleotide synthesis, influencing cell proliferation, migration, and invasion. Beyond RCC, similar activation of serine synthesis occurs in other cancer types, suggesting a shared adaptive response to sunitinib therapy. This research identifies serine synthesis as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/586287v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@47d331org.highwire.dtl.DTLVardef@17a4892org.highwire.dtl.DTLVardef@1329e51org.highwire.dtl.DTLVardef@37de9b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISunitinib induces an increase in endogenous serine production in metastatic ccRCC. C_LIO_LIThe heightened serine biosynthesis promoted by sunitinib facilitates nucleotide synthesis, thereby sustaining tumor cell proliferation. C_LIO_LISunitinib-induced enhancement of serine biosynthesis enables cell migration and invasion. C_LIO_LIThe stimulation in serine synthesis is also observed in other cancer models treated with sunitinib. C_LI