Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma

Abstract

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.

Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

“…S4A–C ). Moreover, consistent with prior studies showing that MEK inhibition up-regulates ERBB2/3 expression ( Sun et al 2014 ) and that MRTX1133 treatment up-regulates ERBB2 expression ( Gulay et al 2023 ), analysis of published xenograft and cell line RNA-seq data ( Hallin et al 2022 ) showed consistent increases in ERBB2/3 expression in diverse KRAS G12D models including PDAC ( Supplemental Fig. S4D,E ).…”

Multi-omics pan-cancer study of SPTBN2 and its value as a potential therapeutic target in pancreatic cancer

“…These findings confirm that SPTBN2 may play a complex immunomodulatory role in the PAAD microenvironment. Another important finding was that SPTBN2 expression correlated with sensitivity to multiple drugs, including Vorinostat (HDAC inhibitor), Afatinib (tyrosine kinase inhibitor), Belinostat (HDAC inhibitor), and Lapatinib (tyrosinase inhibitor) 59 – 61 . Taken together, these findings provide strong evidence that targeting of SPTBN2 in PAAD is warranted and should be further studied.…”

ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC

“…21,22 As K-Ras pathway inhibition impairs glycolysis, forcing cancer cells to rely on OXPHOS for their energetic demands, this mechanism of clinical resistance is expected to impact the entire pharmacological class and is already being reported in laboratory studies of other K-Ras mutant targeting drug candidates. 14,15 For example, K-Ras G12D is the most common K-Ras mutation in PDAC 3 and inhibitors that selectively target K-Ras G12D are currently the subject of Ph I clinical trials in PDAC patients (NCT05737706). We recently demonstrated that acquired resistance to the K-Ras G12D inhibitor MRTX1133 in human PDAC cells is associated with feedback activation of ERBB/AKT signaling and enhanced OXPHOS.…”