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  • For radiochemotherapy it is well known that mitotic cell

    2019-11-07

    For radiochemotherapy, it is well known that mitotic cell death and apoptosis present the major cell death modes. More recently, autophagy-dependent cell death has been described to occur upon radiochemotherapy (Daido et al., 2005, Song et al., 2017). This form of regulated cell death depends on components of the autophagic machinery, which mainly mediate stress DBeQ and cell survival rather than cell death (Fulda and Kögel, 2015, Galluzzi et al., 2018). As many tumors have evolved to resist apoptotic challenges (Hanahan and Weinberg, 2011), modulation of autophagy might be therapeutically exploitable, rendering cancer cells more susceptible to treatment (Galluzzi et al., 2017, Holohan et al., 2013).
    Results
    Discussion GBM remains a tumor type with great unmet need. As intrinsic and acquired resistances to anti-cancer treatment represent universal clinical challenges (Holohan et al., 2013), the unraveling of underlying cellular and microenvironment-driven mechanisms remains of fundamental importance. By considering cell-ECM interactions as key drivers of resistance, we show here that (1) the promitotic and adhesion-mediating receptor tyrosine kinase DDR1 is highly expressed in therapy-resistant GBM stem-like populations, (2) co-expression of DDR1 with GSC markers in clinical samples correlates with patient outcome, (3) inhibition of DDR1 enhances sensitivity and prolongs survival in response to radiochemotherapy with TMZ compared to conventional therapy, and (4) a DDR1-bound 14-3-3-Beclin-1-Akt1 protein complex is required for prosurvival Akt and mTOR signaling and the modulation of autophagy. Prior studies in colorectal, breast, and lung cancer implicate that DDR1 is overexpressed relative to corresponding normal tissues and promotes resistance mechanisms, indicating its potential as a cancer target (Ongusaha et al., 2003). Targeting of DDR1 indeed elicited tumor cell death and prolonged overall survival in cancer mouse models (Ambrogio et al., 2016). Our study confirms these observations in DDR1-overexpressing GBM. While previous studies suggested a relationship between DDR1 expression and patient survival and attributed prognostic and predictive value to DDR1 (Weiner et al., 2000), our study documents an unknown facet of DDR1 as DDR1 expression correlates with expression of the GBM stemness markers such as Nestin and Sox-2 as well as patient outcome. This observation seems of utmost importance for the clinic, where patients receive multimodal therapy for eradicating bulk and stem-like GBM cell populations. In contrast to other studies addressing the cytotoxic effects of single DDR1 targeting, we evaluated the added value of DDR1 targeting on top of radiochemotherapy and showed that DDR1 inhibition is potent to radiochemosensitize GBM cells in vitro and prolong the survival of orthotopic GBM-tumor-bearing mice. Based on the feasibility of this proof-of-concept study with high efficacy and low toxicity, further translational investigations in GBM patients, particularly with regard to the association of DDR1 with the GSC compartment, are warranted. Despite initial hints on how DDR1 contributes to GBM pathogenesis and resistance, the underlying mechanisms are still unsolved. Using broad-spectrum phosphoproteome analysis, we commenced our investigation to untangle DDR1-mediated signal transduction. In addition to modifications in the phosphorylation of well-known GBM drivers like PTEN, EGFR, and PDGFR (Verhaak et al., 2010), we found strong downregulation of the Akt and mTOR axis, including Raptor and Rictor, emphasizing a major role for DDR1 in GBM pathology. Consistent with studies connecting enhanced activity of the Akt and mTOR cascade in GBM with tumor progression and stemness-promoting functions (Mehta et al., 2015), our findings suggest the great advantages of DDR1 targeting in GBM, as resistance-inducing cell adhesion signaling and GBM stemness features are simultaneously interrupted for radiochemosensitization. In addition, we found an increased protein phosphorylation of tyrosine kinases like Pyk2 and FAK, indicating the activation of putative bypass signaling pathways upon DDR1 targeting. For GBM cell radiochemosensitization, these phosphorylation changes seem of minor importance, as DDR1i sufficiently sensitized GBM cells to TMZ and X-ray irradiation. Other kinase inhibitors with an even broader inhibitory spectrum such as imatinib or dasatinib showed some specificity for DDR1 and are promising in the context of DDR1 as a potential cancer target (Ambrogio et al., 2016). Nonetheless, prosurvival bypass signaling for compensation has been observed as a common event upon small-molecule administration and also needs to be addressed for DDR1 inhibitors in future in-depth studies.