The Selective WEE1 Inhibitor Azenosertib Shows Synergistic Antitumor Activity with KRASG12C Inhibitors in Preclinical...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Kirsten rat sarcoma (KRAS) mutations, particularly KRASG12C, are key drivers of cancer, leading to MAPK pathway hyperactivation, replication stress (RS), and DNA damage.
• Resistance to KRASG12C inhibitors can emerge, often maintaining reliance on MAPK signaling and increasing RS.
• High RS creates a vulnerability to cell-cycle checkpoint inhibitors, such as WEE1 kinase inhibitors.

Purpose of the Study:

• To evaluate the combination of a novel WEE1 inhibitor, azenosertib, with KRASG12C inhibitors for treating KRASG12C-mutated cancers.
• To assess the efficacy of this combination in both sensitive and resistant preclinical cancer models.

Main Methods:

• In vitro studies using 2D and 3D cell culture assays with KRASG12C cell lines.
• In vivo studies involving cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.
• Biomarker analysis of RS, DNA damage, and apoptosis markers in tumor samples.

Main Results:

• Azenosertib demonstrated synergistic inhibition of cell growth when combined with KRASG12C inhibitors in vitro.
• In vivo, the combination therapy showed significant synergistic tumor growth inhibition (TGI), including tumor regression in CDX models.
• The combination achieved synergistic TGI even in KRASG12C inhibitor-resistant CDX and PDX models.
• Biomarker analysis confirmed increased RS, DNA damage, and apoptosis following combination treatment.

Conclusions:

• Combining azenosertib with KRASG12C inhibitors enhances anti-tumor activity compared to single-agent therapy.
• This combination strategy shows promise for overcoming resistance and improving treatment outcomes in KRASG12C-driven cancers.
• Further clinical investigation is warranted to establish this combination as a viable therapeutic option.