Numerous factors determine the current poor prognosis of pancreatic ductal adenocarcinoma (PDAC). One of the greatest challenges to overcome is treatment resistance. Among a large repertoire of intrinsic resistance mechanisms, integrin-mediated cell adhesion to extracellular matrix (ECM) has been identified to be fundamental. Coalesced in focal adhesion complexes, integrins, receptor tyrosine kinases, protein kinases and adapter proteins mediate prosurvival signaling. Four and a half LIM domains protein 2 (FHL2) is one of these adapter proteins, which operates through protein-protein interactions and shows tumor-specific expression. Based on this, we investigated FHL2 expression in PDAC specimens and three-dimensionally grown cell lines and how FHL2 mechanistically contributes to cell survival, cell cycling and radiation resistance. PDAC exhibited a significantly increased and heterogeneous FHL2 expression. Upon FHL2 depletion, pancreatic cancer cell lines showed significantly decreased cell survival, proliferation and radioresistance as well as enhanced apoptosis and MEK/ERK signaling and cyclin D1, E, A and B1 expression were strongly induced. Targeting of FHL2 and MEK1 was similarly effective than FHL2 depletion alone, suggesting MEK1 as a downstream signaling mediator of FHL2. Taken together, our results provide evidence for the importance of the focal adhesion protein FHL2 in pancreatic cancer cell survival, proliferation and radiosensitivity.