MYC inhibitors in multiple myeloma

Abstract

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in particular, is a plasma cell malignancy strictly associated with MYC deregulation, suggesting that therapeutic strategies against it would be beneficial in treating this disease. However, targeting MYC was - and, somehow, still is - challenging due to its unique properties: lack of defined three-dimensional structure, nuclear localization and absence of a targetable enzymatic pocket. Despite these difficulties, however, many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition. Different molecules have been tested, in fact, in the context of MM. In this review, we summarize the current status of the different compounds, including the results of their clinical testing, and propose to continue with the efforts to identify, repurpose, redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.

Keywords: MYC downregulation; MYC inhibition; epigenetics; multiple myeloma; targeted therapies; transcription factor; undruggable target.

Figure 1

The response-relapse pattern in multiple myeloma patients. Monoclonal gammopathies that undergo malignant transformation are likely to respond initially to the therapy and enter in remission. However, the disease eventually relapses, and the response becomes less durable until resistance appears, resulting in relapsed refractory myeloma. Figure adapted from^[6]. MGUS: Monoclonal gammopathy of undetermined significance; SMM: smoldering multiple myeloma.

Figure 2

Examples of the most common resistance mechanisms to multiple myeloma therapies. See text for details. For a more thorough description of the resistance mechanisms, check the review from Wallington-Beddoe^[32]. Figure adapted from^[32]. CD38: Cluster of differentiation 38; CRBN: cereblon; ERK: extracellular signal-regulated kinases; IMiDs: immunomodulatory agents; IL-6: interleukin-6; MEK: mitogen-activated protein kinase; RAF: rapidly accelerated fibrosarcoma; SDF-1: stromal cell-derived factor; SLAM7: signaling lymphocytic activation molecule family member 7; TNFα: tumor necrosis factor alpha; Ub: ubiquitin; VEGF: vascular endothelial growth factor.

Figure 3

MYC as a central node in the hallmarks of cancer. MYC is a transcription factor and master regulator of the expression of around 30% of all human genes. As such, it instructs the differential expression of many genes, contributing to the acquisition of cancer-like properties, as defined by Hanahan and Weinberg^[49]. In the image, some examples of MYC target genes involved in the tumorigenesis process are indicated next to the hallmark they impinge on. Figure adapted from^[50].

Figure 4

MYC inhibition strategies at different levels of MYC life cycle. Some examples of drugs are listed. Figure adapted from^[66].