Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL recombinant protein that defines chronic myeloid leukemia (CML) and some forms of acute lymphocytic leukemia (ALL) are currently the standard of care for patients with CML. Patients responding to TKIs are expected to have overall survival (OS) times similar to that of individuals without CML, which is a remarkable achievement in cancer treatment. Nonetheless, several issues remain, principally for the patients who cannot successfully be treated with TKIs due to drug resistance or intolerance. In addition, patients who initially have a good response to TKI therapy may develop secondary mutations that confer treatment resistance; this includes the T315I mutation, which is resistant to all currently approved ABL TKIs and the Src-ABL kinase inhibitor, bosutinib. Another issue is that the vast majority of patients must remain on TKIs indefinitely, as the potential for relapse with treatment discontinuation remains, even for those with deep molecular response.1-3
Inhibiting Autophagy to Enhance TKI Response
A novel treatment strategy for patients with no response or suboptimal response to TKIs is to use a second agent that targets one or more of the mechanisms that tumor cells use to survive. One such approach is to leverage a cellular mechanism called autophagy to enhance TKI efficacy. Autophagy primarily is a cytoprotective mechanism used by cells to isolate and destroy damaged organelles or protein aggregates that can be activated by nutritional insufficiency or growth factor inhibition. Autophagy activation is achieved either indirectly through inhibition of the protein complex mammalian target of rapamycin complex 1 (mTORC1) pathway, which results in activation of ULK1 proteins, or directly through ULK1 phosphorylation by adenosine monophosphate-activated protein kinase (AMPK).4 When activated, ULK1 allows for creation of an isolation membrane that encloses the damaged cell components, which are then degraded by lysosomes.4 As a cytoprotective mechanism, autophagy appears to have evolved as a way for cells to avoid apoptosis in a setting of nutrient deprivation.5
In oncology, the impact of autophagy activation varies by the type of cancer. In some cancers, cytotoxic agents leverage autophagy to destroy tumor cells, whereas in others—including CML—autophagy diminishes the efficacy of anticancer agents by protecting cells from drug-induced apoptosis.4 Drugs that activate or inhibit autophagy have been identified in an interesting variety of drug classes. Examples of those that activate autophagy include mTORC1 inhibitors (eg, rapamycin), metformin (in T-cell ALL cells), and select anticonvulsants (ie, lithium, carbamazepine, valproate). Drugs that inhibit autophagy include chloroquine, which has been shown to destroy essentially all leukemic stem cells when combined with imatinib, dasatinib, or nilotinib, the antimalarial drug hydroxychloroquine (HCQ), and macrolide antimicrobials (eg, azithromycin and clarithromycin).4
Autophagy in CML
In CML treatment, autophagy serves a protective function, as BCR-ABL TKIs activate autophagy through inhibition of the PI3K-AKT-mTORC1 axis—allowing CML cells to avoid apoptosis even when deprived of BCR-ABL.4 Furthermore, TKIs target mature CML cells and do not destroy immature leukemic stem cells, which are intrinsically insensitive to imatinib and second-generation TKIs as a result of overexpression of wild-type p210. Autophagy also promotes survival of leukemic stem cells. Surviving leukemic stem cells are thought to be a major contributor to disease relapse and one of the key factors recommending against TKI discontinuation even when durable molecular responses are achieved.4,6
In CML, autophagy inhibition appears to enhance TKI activity both by potentiating TKI-induced cell death and by eliminating TKI-insensitive stem cells.6 A strategy to enhance TKI activity by combining an ABL TKI with a drug that inhibits autophagy has been validated in a variety of CML cell lines.6
Clinical Research with Alternative Agents
The macrolide antimicrobial clarithromycin inhibits autophagy in tumor cells, but its clinical effect in the setting of TKI resistance is still being explored. A case series of four patients with advanced CML and poor TKI response who were treated with combined TKI and clarithromycin showed promising results. These patients had been, or were currently being treated with, imatinib, dasatinib, or nilotinib (one patient had received all three agents) and most had received interferon-alfa/cytarabine or other therapies. None had achieved molecular response on previous therapy. The addition of clarithromycin to their TKI regimen led to a response in all four patients. Further proof of principle was obtained when three patients stopped the antimicrobial and experienced disease progression. Reintroduction of clarithromycin led to clinical improvement in two of three patients.5,7,8 In a separate study, clarithromycin has also been shown to enhance dasatinib activity.9
HCQ, which is related to chloroquine but with less toxicity, has been used in oncology in combination with cytotoxic chemotherapy or radiation therapy.10 A phase 2 study based in the United Kingdom currently is underway to evaluate whether the addition of HCQ to imatinib improves response when patients with CML have achieved major cytogenetic response on imatinib but still have measurable residual disease. Patients are randomly assigned to receive imatinib once daily or imatinib once daily plus HCQ twice daily for up to 12 months, and will be stratified by imatinib response (< 3 logs or ≥ 3 logs below baseline BCR-ABL transcript levels), time on imatinib, and initial imatinib dose.11
Even if autophagy inhibition proves successful in enhancing TKI response, both types of drugs have additional actions that need to be evaluated and assessed in large-scale trials before their widespread use could be recommended in long-term antitumor therapy.
Autophagy inhibition is an active area of research as clinicians explore new avenues to improve TKI response in CML, overcome secondary resistance, and potentially achieve lasting cures that allow treatment discontinuation. Results from small case series are encouraging, but further large-scale research is needed to elucidate the potential of this novel approach to CML treatment.
- Sinclair A, Latif AL, Holyoake TL. Targeting survival pathways in chronic myeloid leukaemia stem cells. Br J Pharmacol. 2013;169(8):1693-1707.
- Keller-von Amsberg G, Schafhausen P. Bosutinib in the management of chronic myelogenous leukemia. Biologics. 2013;7:115-122.
- Mahon F-X, Rea D, Guilhot J, et al. Long-term follow-up after imatinib cessation for patients in deep molecular response: the update results of the STIM1 study. Presented at the 55th Annual Meeting of the American Society of Hematology; December 5-10, 2013; New Orleans, LA. Abstract 255.
- Nencioni A, Cea M, Montecucco F, et al. Autophagy in blood cancers: biological role and therapeutic implications. Haematologica. 2013;98(9):1335-1343.
- Altman JK, Platanias LC. A new purpose for an old drug: inhibiting autophagy with clarithromycin. Leuk Lymphoma. 2012;53(7):1255-1256.
- Bellodi C, Lidonicci MR, Hamilton A, et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest. 2009;119(5):1109-1123.
- Carella AM, Beltrami G, Pica G, et al. Clarithromycin potentiates tyrosine kinase inhibitor treatment in patients with chronic myeloid leukemia. Leuk Lymphoma. 2012;53(7):1409-1411.
- Carella AM, Beltrami G, Pica G, et al. Clarithromycin enhances tyrosine kinase inhibitor–induced cell death by inhibition of late stage autophagy in patients with chronic myeloid leukemia at diagnosis or with resistant stage of disease. Poster presented at the 54th Annual Meeting of the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Abstract 3777.
- Schafranek L, Leclercq TM, White DL, Hughes TP. Clarithromycin enhances dasatinib-induced cell death in chronic myelogenous leukemia, by inhibition of late-stage autophagy. Leuk Lymphoma. 2013;54(1):198-201.
- Mukhopadhyay A, Helgason GV, Karvela M, Holyoake TL. Hydroxychloroquine for chronic myeloid leukemia: complete cure on the horizon? Expert Rev Hematol. 2011;4(4):369-371.
- ClinicalTrials.gov. CHOICES: A randomized phase II trial of imatinib versus hydroxychloroquine and imatinib for patients with chronic myeloid leukemia in major cytogenetic response with residual disease detectably by quantitative polymerase chain reaction. http://clinicaltrials.gov/ct2/show/NCT01227135?term=CHOICES+IMATINIB&rank=3. Accessed December 13, 2013.