At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4th April, a poster session titled “Targeting Protein Kinases and DNA Repair” took place.
One of the posters on display (4192 / 15) was titled “Targeting SHP-1/p-Lyn signaling shows therapeutic potential in diffuse large B-cell lymphoma” by Chun-Yu Liu from Taipei Veterans General Hospital, Taipei, Taiwan, and colleagues.
The group aimed to investigate the biological role and potential therapeutic implication of SHP-1, a protein phosphatase, in DLBCL. In vitro studies used ABC-like cell lines U2932 and Ly-3, as well as GC-like cell lines DHL-6, Ly-7, and DB. Nude mice with DLBCL xenografts were used for in vivo therapeutic testing of AHP-1 agonists.
- Ln general, SHP-1/p-STAT3 expression was higher in ABC-like cells
- Expression of p-Lyn (Tyr396) and p-BTK (Tyr223), key components of the BCR signaling pathway, were higher in ABC-like cells
- Knockdown or overexpression of SHP-1 expression caused a reciprocal change of p-Lyn; indicates SHP-1 negatively regulates Lyn kinase phosphorylation
- Immunoprecipitation experiments confirmed SHP-1 interacts with Lyn in DLBCL cells
- Then tested SHP-1 agonists (SC-43 and SC-60) versus ibrutinib
- In general, SHP-1 agonists showed superior anti-proliferative and apoptotic effects vs ibrutinib
- Mechanistically, SHP-1 agonists enhanced SHP-1 activity, decreased BCR signaling by p-Lyn and p-BTK, which led to apoptosis
- SHP-1 agonists found to down-regulate p-STAT3, also contributing anti-cancer effects
- In mice bearing U2932 xenografts, SC-43 administered orally at 10mg/kg/day and 30mg/kg/day demonstrated similar anti-tumor effects as ibrutinib at doses of 12.5mg/kg/day and 25mg/kg/day, respectively
- Western blot confirmed SC-43 mediated down-regulation of p-Lyn and p-BTK in vivo
The poster was concluded by stating that phosphorylation of Lyn is negatively regulated by SHP-1. Using SHP-1 agonists to target SHP-1/p-Lyn demonstrated therapeutic potential in DLBCL in vivo and in vitro models.