A new purpose for an old drug: inhibiting autophagy with clarithromycin

There is substantial evidence that the process of autophagy plays key roles in cancer development [1]. Autophagy is a coordinated cellular process in which cells become less dependent on nutrient metabolism. While autophagy can serve as a mechanism of cell death, it is now understood that this process is also utilized as a cell survival mechanism by allowing cells to adapt to nutrient deprivation so they can evade apoptosis [1]. Pharmacological or molecular targeting of elements of the autophagic process has been shown under certain circumstances to lead to apoptosis and/or enhance the antineoplastic effects of other agents [2,3]. The translational relevance and importance of this phenomenon has been demonstrated in several models, including an animal model of lymphoma, in which the addition of autophagy inhibitors increased the potency of chemotherapy [4].

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Many patients have long-standing remissions after treatment with imatinib mesylate. However, resistance develops in some patients, frequently secondary to BCR–ABL kinase domain mutations [5,6]. Previous work has established that treatment with imatinib mesylate results in autophagy in CML cells [2]. Inhibition of autophagy with pharmacological inhibitors enhanced the effects of imatinib mesylate on BCR–ABL expressing cells, including cells with mutations resulting in imatinib resistance [2]. This has suggested that maneuvers to inhibit autophagy may restore disease sensitivity in patients with CML that has become refractory to the available tyrosine kinase inhibitors.

Clarithromycin is a macrolide antibiotic frequently utilized in the treatment of upper and lower respiratory tract infections and Helicobacter pylori [7]. In addition to its antibacterial properties, laboratory studies have demonstrated that the drug inhibits autophagy in malignant cells [8]. It remains to be seen whether the inhibitory effects of clarithromycin on autophagy can translate to therapeutic approaches to enhance antitumor responses. A case-matched analysis comparing patients with newly diagnosed multiple myeloma who received low-dose dexamethasone and lenalidomide with or without clarithromycin was conducted by Gay and colleagues [9]. The complete response rate and progression-free survival were significantly higher for the group treated with clarithromycin [9]. The authors hypothesized that the increase in response rate seen with clarithromycin was secondary to enhancement of the effects of glucocorticoids, based on prior studies of clarithromycin and steroids in asthma [10]. However, although this was not specifically examined in that study, it is possible that other mechanisms, including inhibition of autophagy, were involved. There are also other active studies of clarithromycin in malignancy. These include a phase II trial of single-agent clarithromycin in indolent lymphoma [11] and clarithromycin in combination with lenalidomide and dexamethasone for patients with multiple myeloma that has recurred after stem cell transplant [12].

In this issue of Leukemia and Lymphoma, Carella et al. describe a series of four patients with advanced CML whose disease was not adequately controlled by TKIs [13]. They report that the addition of clarithromycin restored the sensitivity of their disease to TKIs. Three patients in the series stopped clarithromycin, and all experienced CML disease progression after clarithromycin discontinuation. When clarithromycin was reintroduced, two of the three patients had improvement in disease burden. These results are preliminary, especially as the mechanism of the responses to clarithromycin were not established in these studies. Nevertheless, they are intriguing, and may have important clinical implications. One might argue that restoring disease sensitivity to imatinib may not be important with the advent of dasatinib, nilotinib, bosutinib and/or ponatinib [5]. However, there are instances where even the second-generation TKIs are not effective, and this report suggests that inhibition of autophagy may provide an attractive approach to increase TKI sensitivity. It is also possible that autophagy inhibition may result in elimination of leukemia-initiating stem cells as suggested by the preclinical work of Bellodi et al. [2]. Randomized clinical trials with autophagy inhibitors and associated correlative studies will provide a deeper understanding of the importance of autophagy inhibition in CML and further elucidate the biology of TKI resistance in this disease.

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