bioRxiv Science⌕ Search

Biology subjects

Giuliano, S.

Publications and source records attributed to Giuliano, S..

2 recordsLinked to original sources
bioRxiv2024

Exploiting De Novo Serine Synthesis as a Metabolic Vulnerability to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma

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

cancer biology↗
bioRxiv2018

Pharmacological inhibition of the amino-acid transporter LAT1 demonstrates in vitro anti-neoplastic activity towards medulloblastoma

Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, the present study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.

cancer biology↗