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  • Autophagy also plays a role in

    2018-11-05

    Autophagy also plays a role in response to treatment. An extensive literature suggests that autophagy can protect cancer cells against commonly used cancer therapies including a wide array of different drugs and radiation (Thorburn et al., 2014; Rebecca and Amaravadi, 2015). Such studies are the basis for most of the current efforts to target autophagy in patients (Table 2). Perhaps even more important than chemo-sensitization, autophagy inhibition may overcome acquired resistance to other anti-cancer agents. The best evidence for this is in tumors with activating mutations in BRAF that have become resistant to BRAF inhibitors like vemurafenib. Vemurafenib resistance in melanoma is associated with increased autophagy and autophagy inhibition can reverse resistance associated with endoplasmic reticulum stress (Ma et al., 2014). There is also evidence that autophagy inhibition to overcome drug resistance can be effective in patients. A shk cancer patient with a BRAF mutant tumor that had become resistant to vemurafenib was successfully treated with a combination of CQ and vemurafenib experiencing long term tumor regression on the combination treatment (Levy et al., 2014). Importantly, this patient had periods of time when the autophagy inhibitor CQ was maintained but the BRAF inhibitor was discontinued for periods of time. In every instance, this led to increased tumor growth that was reversed when the combination treatment was re-established. This case study is the first to suggest that autophagy inhibition with CQ can overcome acquired resistance to the kinase inhibitor but that only combination treatment with both the BRAF inhibitor and the autophagy inhibitor is effective. Continued follow up of this patient has demonstrated sustained tumor regression for over two and a half years and more recent studies submitted for publication from Mulcahy-Levy et al. have extended these findings to two other patients both of whom acquired resistance to vemurafenib following successful therapy and then experienced clinical improvement on the combination of CQ and vemurafenib. Although most current clinical trials (Table 2) involve autophagy inhibition, there are arguments against this idea often revolving around effects of autophagy inhibition on the immune response to cancer (Zhong et al., 2016). It has been reported that “immunogenic” tumor cell killing– i.e. killing cancer cells with chemotherapy in a way that will lead to effective engagement of an anti-tumor immune response – requires that the dying cancer cells have functional autophagy (Michaud et al., 2011) leading to suggestions that we should try to enhance autophagy to improve cancer immunotherapy (Zhong et al., 2016). Consistent with this idea, a recent study concluded that caloric restriction could enhance tumor immunosurveillance only for autophagy-proficient tumors (Pietrocola et al., 2016). However, autophagy inhibition can enhance immune cell-mediated, anti-tumor effects under at least some circumstances (Liang et al., 2012; Baginska et al., 2013). More work is needed to better understand the interplay between autophagy\'s role(s) in the anti-tumor immune response.
    Clinical Trials of Targeted Autophagy Inhibition Despite the caveats discussed above, there are already many studies attempting to inhibit autophagy in cancer therapy. All the current studies use CQ or HCQ. These drugs inhibit the lysosome and block autophagy while causing accumulation of autophagosomes and LC3, which have been used as pharmacodynamic markers of the inhibitor\'s activity. CQ and HCQ are inexpensive, approved drugs that have been used for decades to treat malaria and arthritis but have some caveats as autophagy inhibitors. First, they can have anti-tumor effects through other mechanisms such as reducing nutrient scavenging and can sensitize to other chemotherapies by autophagy-independent mechanisms (Eng et al., 2016; Maycotte et al., 2012). Second, alterations in tumor pH may affect drug bioavailability (Pellegrini et al., 2014).