Abstract 2938: KRAS and ERK5 signaling pathways in cancer: Implications for targeted therapy.

Abstract KRAS Signaling in Cancer: KRAS functions as a small GTPase that serves as a molecular switch in cellular signaling, orchestrating proliferation, differentiation, and survival mechanisms. As the central node of the RTK-RAS-RAF-MEK-ERK signaling cascade, KRAS mutations represent the most frequent oncogenic events across human cancers, particularly in pancreatic, colorectal, and lung malignancies. These mutations drive constitutive pathway activation, promoting uncontrolled cellular growth. In lung cancer, KRAS G12C mutations are especially prevalent, leading to the development and approval of targeted therapies such as Sotorasib and Adagrasib. The clinical success of these KRAS G12C inhibitors has established a promising foundation for developing additional molecules targeting various K/N/H RAS isoforms. ERK5 Signaling and Cancer Progression: ERK5, another member of the MAPK family, is activated by MEK5 in response to mitogenic and stress signals. The MEK5-ERK5 pathway regulates critical physiological and pathological processes, including cell survival and proliferation. Additionally, this signaling axis plays significant roles in metastatic progression and immune modulation within tumor microenvironments. Notably, inhibition of the RAS pathway frequently triggers compensatory upregulation of MEK5-ERK5 signaling, enabling cancer cells to maintain oncogenic signaling despite targeted intervention. Research Focus: In this investigation, we will establish an ERK5 transcriptional gene signature and demonstrate how broad RAS pathway inhibition leads to ERK5 signaling overactivation through multiple experimental approaches. Citation Format: Christophe Marcireau, Fréderic Lacroix, Fatima Amor, Karine Dobrazix, Guillaume Nurit, Véronique Jean-Baptiste, Eiwen Yang, Donald Jackson, Colette Dib, Gaelle Muzard, Franck Slowinski, Laurent Debussche, Pawel K. Mazur. KRAS and ERK5 signaling pathways in cancer: Implications for targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2938.