PIKing the next therapeutic target in multiple myeloma

Arguably the most transformative myeloma therapies to date have been those which target essential processes involved in plasma cell function. Although their mechanism of action may not have been entirely obvious when first introduced, it has now become clear from cell-based studies that these therapies target protein degradation via the ubiquitin proteasome pathway, a critical process for plasma cell survival. Examples include proteasome inhibitors (such as bortezomib, carfilzomib, and ixazomib) and the immunomodulatory drugs (such as lenalidomide and pomalidomide), which inhibit the CUL4 E3 ubiquitin ligase, cereblon. Both drug classes are the ‘go to’ choices in current myeloma treatment.1 It therefore comes as no surprise that the search for other therapies targeting protein degradation pathways continues.

The key function of a normal plasma cell is to produce immunoglobulins. Studies have shown that myeloma plasma cells, which produce large quantities of M protein, are highly dependent on the multiple pathways that enable a cell to handle excess unfolded or misfolded proteins. Over the last 10 years, cancer researchers have explored many of these pathways with a view to therapeutic exploitation. The rationale is that inhibition of these pathways leads to a build up of unwanted or misfolded proteins, the induction of cellular stress, and ultimately to cancer cell death. Such pathways include not only the ubiquitin proteasome pathway but also the heat shock protein pathway, autophagy pathway, unfolded protein response pathway, and pathways involving lysosomes and aggresomes.2 However, translating in vitro findings into clinical success has been difficult. It has become clear that some cancer types are dependent on one pathway more than others, the pathways are interlinked, and the crosstalk between pathways enables the development of both primary and drug-induced mechanisms of resistance.

In this edition of Haematologica, Bonolo de Campos et al. describe a promising new approach for myeloma therapy by perturbing the autophagy and lysosome pathways.3 In autophagy, misfolded and aggregated proteins are sequestered in double-membraned vesicles called autophagosomes that eventually fuse with lysosomes for digestion and recycling. Previous studies have shown that myeloma cells require tight regulation of the autophagy pathway for cell survival, and genetic or therapeutic manipulation of this pathway induces growth inhibition and/or cell death.542

Phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) is a phosphoinositide kinase with many diverse functions within the cell, including the generation of phosphorylated substrates critical to the regulation of autophagy.6 Inhibition of PIKfyve using the selective inhibitor apilimod has previously been investigated as a potential therapeutic approach for both inflammatory diseases and non-Hodgkin lymphoma.7 Using an unbiased chemical screen, Bonolo de Campos et al. identified APY0201 and examined its activity along with that of apilimod and another novel PIKfyve inhibitor YM201636 in 25 human myeloma cell lines and 100 ex-vivo patient-derived samples. They confirmed dose-dependent inhibition of cell viability in all myeloma cell lines, with APY0201 being the most potent PIKfyve inhibitor. They additionally observed dose-dependent sensitivities in 40% of ex-vivo patient-derived samples with APY0201. Mechanistic experiments suggested that exposure to APY0201 resulted in activation of the transcription factor EB (TFEB) leading to upregulation of autophagosome and lysosomal biogenesis. Exposure also disrupted lysosomal function leading to alterations in autophagic flux and a vacuolization phenotype.

As myeloma is a genetically and biologically heterogeneous disease, it is critical to identify which patients would benefit most from a new therapy. The prime example of the need for such an approach is venetoclax, a Bcl-2 inhibitor, which has been shown to be particularly efficacious in patients harboring a t(11;14) translocation.8 Although targeting a pathway central to plasma cell survival should theoretically result in universal myeloma cell death, it has become clear that the genetic background of the cell influences response to therapy.9 For instance, whereas patients with a t(14;16) translocation tend to respond poorly to proteasome inhibitors, these therapies may be able to overcome some of the adverse outcome associated with the t(4;14) subgroup.10 Therefore, trying to incorporate genetic information into therapeutic decision-making may allow us to optimize treatment choices and response rates and to provide long-lasting remissions. Importantly, the authors have tried to assess this in their study using data from the patients’ samples. The activity of APY0201 was highest in patient-derived samples with hyperdiploidy (trisomies with one or more odd-numbered chromosomes) and lowest in patients’ samples with a t(11;14) translocation. In addition, ex-vivo samples with high TFEB levels were sensitive to APY0201. High TFEB levels have been associated with increased autophagic flux suggesting that autophagic flux may be directly related to PIKfyve inhibition. These preliminary results may suggest patient populations that could be enriched for in a future clinical trial.

In conclusion, Bonolo de Campos et al. provide exciting data to support the ongoing investigation of therapeutically manipulating targets specific to plasma cell function, particularly protein handling in myeloma.2 Although the finer details of the actual mechanisms may differ somewhat between multiple myeloma and non-Hodgkin lymphoma, data from this study and those performed in non-Hodgkin lymphoma provide compelling evidence for the role of PIKfyve inhibition in inducing cell death, with changes seen in the autophagy and lysosomal pathways. Notably, this study demonstrates the importance of the inherent genetic differences in myeloma biology and the potential role of PIKfyve inhibitors in targeting a distinct group of genetically defined myeloma to continue this era of personalized medicine.