Mouse pancreatic tumors were significantly smaller after being treated with a combination of KRAS inhibitor MRTX1133 and ERBB inhibitor Afatinib (bottom row), compared to no treatment (top row) or being treated with Afatinib (second row) or MRTX1133 (third and fourth rows) alone.
膵管腺癌におけるKRASG12Dと汎ERBBの二重阻害が相乗効果を示す Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma
Kevin Christian Montecillo. Gulay,Xinlian Zhang,Vasiliki Pantazopoulou,Jay Patel,Edgar Esparza,Deepa Sheik. Pran Babu,Satoshi Ogawa,Jonathan Weitz,Isabella Ng,Evangeline S. Mose,Minya Pu,Dannielle D. Engle,Andrew M. Lowy,Hervé Tiriac
Cancer Research Published:JUNE 28 2023
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.