A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

Shayan Khalafi, Shoumin Zhu, Rimpi Khurana, Ines Lohse, Silvia Giordano, Simona Corso, Hassan Al-Ali, Shaun P. Brothers, Claes Wahlestedt, Stephan Schürer, Wael El-Rifai

Research output: Contribution to journalArticlepeer-review

Abstract

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 (γH2AX) 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.

Original languageEnglish (US)
Article number101260
JournalTranslational Oncology
Volume15
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • Clofarabine
  • Combination therapy
  • Drug synergy
  • Gastric cancer
  • Pictilisib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer'. Together they form a unique fingerprint.

Cite this