Fig. 3
From: The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer
Molecular model of cell signaling in CCDC6 unperturbed condition (a) and upon CCDC6 fusion to the tyrosine kinase (ie RET) (b). a) In CCDC6 unperturbed condition. i) CCDC6 can complex with CREB1 and the phosphatase PP1, keeping CREB1 in an inactive state for the transcription of Amphiregulin (AREG). ii) CCDC6 can promote the maintenance of phosphorylated H2AX, on S139, in the foci of DNA Damage Repair (DDR) by holding back the histone H2AX specific PP4C phophatase, allowing the correct DNA repair process. b) Upon CCDC6 fusion to the kinase (ie RET). i) the chimeric oncogene CCDC6/TK forms homodimers which activate the MAPK/ERK cascade. ii) the chimeric oncogene CCDC6/TK forms heterodimers with the wild-type CCDC6 protein which act as dominant negative on CCDC6 nuclear localization and function. In this condition CCDC6, unable to repress CREB1 activity, results in an autocrine loop of AREG for the autonomous activation of EGFR and MAPK/ERK cascade. Moreover, in this condition CCDC6 is unable to hold back the PP4C phosphatase directed towards the de-phosphorylation on S139 of the histone H2AX in response to DNA damage (DDR), leading to an uncorrect repair of the Double Strand Breaks (DSBs) in the TK activated cancer cells. On these bases, hypothetical innovative therapeutic approach are suggested