Abstract A091: The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors
Authors: Coma Silvia , Liu Xiuting , Pieper Noah L. , Chang Wen-Hsuan , Bryant Kirsten L. , Der Channing J. , DeNardo David G. , Pachter Jonathan A. 
Published: January 2024

Abstract
KRAS mutations (mt) occur in up to 98% of pancreatic ductal adenocarcinoma (PDAC) and represent a key initiating event in PDAC carcinogenesis. Therapeutic efforts targeting the RAS/RAF/MEK/ERK (MAPK) pathway with MEK-only inhibitors have been unsuccessful in substantially modifying PDAC prognosis. Thus, novel strategies are needed to overcome putative mechanisms of resistance to MEK inhibition such as focal adhesion kinase (FAK) pathway activation. Another hallmark of PDAC is its high stromal density, which is thought to limit the penetration of cytotoxic drugs and T cells into the tumor and has been shown to be correlated with FAK hyperactivation, altogether supporting co-targeting the MAPK and FAK pathways to achieve deep and durable responses for patients with PDAC. Avutometinib is a RAF/MEK clamp that potently inhibits MEK kinase activity and induces dominant negative RAF-MEK complexes preventing phosphorylation of MEK by ARAF, BRAF and CRAF. This unique mechanism allows avutometinib to block MEK signaling without the compensatory re-activation of MEK that appears to limit the efficacy of MEK-only inhibitors. Preclinically, avutometinib has shown strong anti-proliferative potency across tumor cell lines carrying KRAS mt including PDAC cell lines. Clinically, avutometinib in combination with the FAK inhibitor (FAKi) defactinib received breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer. Here, we tested the combination of avutometinib and FAK inhibition with standard of care chemotherapy in PDAC mouse models. In a KRAS/p53 pancreatic cancer mouse model, we found that whereas the combination of avutometinib + FAKi induced tumor inhibition and increased survival, addition of chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) to avutometinib/FAKi induced tumor regression. These results support the ongoing clinical study of avutometinib and defactinib in combination with standard of care chemotherapy (gemcitabine/nab-paclitaxel) for patients with front-line metastatic PDAC (NCT05669482). Other combinations being explored preclinically include avutometinib with G12D inhibition (G12Di) in KRAS G12D PDAC, which accounts for 28% of patients with PDAC. In 3D culture, avutometinib was synergistic with the G12Di MRTX1133 in reducing viability of a panel of KRAS G12D PDAC cell lines. In mouse models, avutometinib enhanced anti-tumor efficacy of MRTX1133 in a KRAS G12D pancreatic cancer patient-derived xenograft model. Furthermore, in KRAS mt PDAC cell lines, avutometinib was synergistic with the autophagy inhibitors chloroquine or apilimod. Indeed, dual treatment with avutometinib + MRTX1333 synergistically decreased proliferation and increased autophagic flux in KRAS G12D PDAC cell lines, supporting testing the triple combination of avutometinib + G12Di + autophagy inhibitor in patients with KRAS G12D pancreatic cancers. In conclusion, we show that avutometinib is a unique RAF/MEK clamp with the potential to become the backbone of therapy for pancreatic cancers.
Citation Format: Silvia Coma, Xiuting Liu, Noah L. Pieper, Wen-Hsuan Chang, Kirsten L. Bryant, Channing J. Der, David G. DeNardo, Jonathan A. Pachter. The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A091.