Unfolding tyrosine kinase inhibitor sensitivity in chronic myeloid leukemia

The unfolded protein response (UPR) is a mechanism by which normal cells react to endoplasmic reticulum (ER) stress to maintain cell homeostasis. ER stress is triggered by a variety of stimuli, including nutrient deprivation, oxidative stress and higher metabolic demand. This often results in the accumulation of unfolded or misfolded proteins in the ER lumen, a phenomenon that triggers the switch-on of the UPR. Thus, a complex network of pathways will act together to protect, adapt and recover the “injured” cells from ER stress.¹ At molecular level, this translates into inhibition of protein translation and enhanced transcription of genes encoding molecular chaperones and other factors important for protein folding, degradation and quality control.¹ If the damage to the ER persists over a prolonged period of time, apoptosis is normally evoked to eliminate damaged cells.² Because cancer cells are generally exposed to a multitude of internal and external metabolic stressors, it is not surprising that molecular pathways regulating the cell response to ER stress have been found associated with autophagic and antiapoptotic signals and aberrantly activated in solid tumors and leukemias,^1,3 two characteristics that make this pathway suitable to be used for therapeutic intervention. For example, a suitable target for anticancer drug development is represented by the ER chaperone GRP78; in fact, its high level of expression in a variety of tumors, including hepatocellular carcinoma, breast cancer and chronic myeloid leukemia (CML), is a strong indicator of a deregulated and, likely, constitutively active UPR.^1,3-6

CML is characterized by the presence of the Philadelphia chromosome carrying the fusion oncogene BCR-ABL1.⁷ The presence of this constitutively active tyrosine kinase in myeloid progenitors is sufficient to induce and maintain their enhanced survival, a feature that is typical of the prolonged and indolent chronic phase (CP) of CML.⁷ While in the mid-’90s allogeneic stem cell transplantation was the only curative, albeit risky, option for CML, from early 2000, first- and second- and, soon, third-generation TKIs (i.e., imatinib, nilotinib, dasatinib, bosutinib and ponatinib) are the elective therapeutic choice for chronic phase patients, the majority of which achieve and maintain major or complete molecular response.⁷ However, in a small percentage of patients that are either refractory or become resistant to ABL1 tyrosine kinase inhibitors, CML undergoes blastic transformation, a still-fatal disease stage, historically termed blast crisis (BC) that is characterized by the increased expression and/or activity of BCR-ABL1 and the accumulation of secondary genetic and molecular abnormalities.⁷ Thus, it is therefore imperative to explore alternative routes that may be helpful to prevent the arising of resistance to TKIs and, most importantly, offer patients in CML-BC new-targeted therapeutic options that may either eliminate the leukemic cell clone or make it responsive to TKIs and other available drugs.

In a recent issue of Cell Cycle, Kusio-Kobialka et al.⁸ describe for the first time that in CML there is a correlation between ER stress, CML progression and response to imatinib treatment. In particular, they found that in human CML cell lines and primary cells, the PKR-like ER-resident kinase (PERK) is activated in a BCR-ABL1 expression-dependent manner.⁸ PERK is one of the main initiators of the UPR and PERK-dependent phosphorylation of eIF2α impairs global cap-dependent mRNA translation, with the exception of ATF4 mRNA, whose product activates pathways controlling adaptation to stress and apoptosis.¹ Importantly, the activation of the PERK-eIF2α pathway seems to follow the natural progression of the disease and is enhanced in cells derived from patients in CML-BC as opposed to patients in the chronic phase or to cells derived from healthy individuals.⁸ When BCR-ABL1-expressing cells were treated with imatinib, the authors saw a downregulation of PERK and eIF2α expression and phosphorylation levels in a dose-dependent manner, suggesting that the induction of the response to the ER stress may be mediated by BCR-ABL1 activity.⁸ By using dominant-negative mutants of PERK or eIF2α, the authors have also been able to show that the PERK-eIF2α pathway serves a pro-survival role in CML; in fact, cells expressing their dominant-negative forms show a decreased ability to form colonies in clonogenic assays and also seem to be more sensitive to imatinib-mediated cell death.⁸ In conclusion, this manuscript highlights the importance of exploring alternative pathways, like those involved in the UPR, as they might constitute the answer to overcoming the current therapeutic limitations we are facing in treating CML-BC and other acute leukemia patients.

Kusio-Kobialka M, Podszywalow-Bartnicka P, Peidis P, Glodkowska-Mrowka E, Wolanin K, Leszak G, Seferynska I, Stoklosa T, Koromilas AE, Piwocka K. The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. Cell Cycle. 2012;11:4069–78. doi: 10.4161/cc.22387.