The vast majority of our knowledge regarding
cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam
radiation therapy (EBRT). Yet, less is known about the
cancer response to internal targeted
radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled
minigastrin analogue [177Lu]Lu-PP-F11N (β-emitter) and EBRT (ɣ-rays) in CCKBR-positive
cancer cells. Activation of DNA damage response by p53 was induced by both types of
radiotherapy, whereas TRT robustly increased activation of signaling pathways including
epidermal growth factor receptor (EGFR),
mitogen-activated protein kinases (MAPKs) or
integrin receptor. Inhibition of EGFR or
integrin signaling sensitized
cancer cells to radiolabeled
minigastrin. In vivo, EGFR inhibitor
erlotinib increased therapeutic response to [177Lu]Lu-PP-F11N and median survival of A431/CCKBR-
tumor bearing nude mice. In summary, our study explores a complex scenario of
cancer responses to different types of irradiation and pinpoints the radiosensitizing strategy, based on the targeting survival pathways, which are activated by TRT.