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[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling

Laurence Booth1, Jane L Roberts1, Mehrad Tavallai1

  • 1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.

Oncotarget
|March 26, 2016
PubMed

Insights

Combining pemetrexed and sorafenib showed promise in a phase I trial. Pre-clinical studies reveal that adding an ERBB1/2/4 inhibitor significantly enhances anti-tumor effects by blocking key signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Pharmacology

Background:

  • A phase I trial combining pemetrexed and sorafenib demonstrated promising results in solid tumors.
  • Tumor resistance and regrowth after initial treatment necessitate strategies for enhanced efficacy.
  • Understanding resistance mechanisms is crucial for optimizing combination therapies.

Purpose of the Study:

  • To identify signaling modulators that can enhance cell killing induced by pemetrexed and sorafenib.
  • To investigate the molecular mechanisms underlying tumor resistance to pemetrexed and sorafenib.
  • To evaluate the in vivo efficacy of combining pemetrexed, sorafenib, and ERBB inhibitors.

Main Methods:

  • Multiplex assays on post-treatment tumor material to analyze signaling pathways.
  • Inhibition of specific kinases (JAK1/2, ERBB1/2/4) and gene knockdown (ERBB1/2/3) to assess their role in cell killing.
  • In vivo studies using established mammary and NSCLC tumors treated with drug combinations.
  • Analysis of chaperone protein activity and client interactions.

Main Results:

  • Inhibition of ERBB1/2/4, but not JAK1/2, significantly enhanced pemetrexed + sorafenib-induced cell killing.
  • ERBB1/2/4 inhibition blocked NFκB activation and SOD2 expression, while IκB S32A S36A expression enhanced lethality.
  • Sorafenib inhibited HSP90/70 ATPase activity and client protein interactions.
  • In vivo, transient exposure to ERBB inhibitors (lapatinib, vandetanib, afatinib) significantly enhanced the anti-tumor effect of pemetrexed + sorafenib without apparent toxicity.

Conclusions:

  • Targeting ERBB1/2/4 is a rational strategy to enhance the efficacy of pemetrexed and sorafenib.
  • The combination of pemetrexed, sorafenib, and an ERBB1/2/4 inhibitor warrants further clinical investigation.
  • This combination strategy shows potential for treating solid tumors, including breast cancer and NSCLC.
Keywords:
ERBB1PTENpemetrexedsorafenib

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