BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers

Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Scott E. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou

Research output: Contribution to journalLetterpeer-review

4 Scopus citations

Abstract

KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-XL proteolysis targeting chimera [PROTAC]) on KRASG12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.

Original languageEnglish (US)
Article number23
JournalJournal of Hematology and Oncology
Volume15
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • BCL-X
  • Drug resistance
  • KRAS
  • PROTAC
  • Sotorasib

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers'. Together they form a unique fingerprint.

Cite this