Journal
TRANSLATIONAL ONCOLOGY
Volume 15, Issue 1, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.tranon.2021.101260
Keywords
Clofarabine; Pictilisib; Gastric cancer; Drug synergy; Combination therapy
Categories
Funding
- U.S. National Institutes of Health [R01CA249949, T32 CA211034, LINCS-DCIC U54HL127624]
- National Cancer Institute [P30CA240139]
- U.S. Department of Veterans Affairs [1IK6BX003787, I01BX001179]
- Sylvester Comprehensive Cancer Center Support Grant [P30CA240139]
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The combination therapy of clofarabine and pictilisib in gastric cancer promotes DNA damage and inhibits key cell survival pathways to induce cell death more effectively than single-agent treatment.
Gastric cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) approved compounds and identified clofarabine as a potential therapeutic agent. RNA-sequencing (RNAseq) of clofarabine treated GC cells was analyzed according to our SynergySeq pipeline and identified pictilisib as a potential synergistic agent. Clonogenic survival and Annexin V assays demonstrated increased cell death with clofarabine and pictilisib combination treatment (P<0.01). The combination induced double strand breaks (DSB) as indicated by phosphorylated H2A histone family member X (gamma H2AX) immunofluorescence and western blot analysis (P<0.01). Pictilisib treatment inhibited the protein kinase B (AKT) cell survival pathway and promoted a pro-apoptotic phenotype as evidenced by quantitative real time polymerase chain reaction (qRT-PCR) analysis of the B-cell lymphoma 2 (BCL2) protein family members (P<0.01). Patient derived xenograft (PDX) data confirmed that the combination is more effective in abrogating tumor growth with prolonged survival than single-agent treatment (P<0.01). The novel combination of clofarabine and pictilisib in GC promotes DNA damage and inhibits key cell survival pathways to induce cell death beyond single-agent treatment.
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