Chromosomal instability and acquired drug resistance in multiple myeloma

Abstract

Chromosomal instability (CIN) is an important hallmark of human cancer. CIN not only contributes to all stages of tumor development (initiation, promotion and progression) but also drives, in large measure, the acquisition of drug resistance by cancer cells. Although CIN is a cornerstone of the complex mutational architecture that underlies neoplastic cell development and tumor heterogeneity and has been tightly associated with treatment responses and survival of cancer patients, it may be one of the least understood features of the malignant phenotype in terms of genetic pathways and molecular mechanisms. Here we review new insights into the type of CIN seen in multiple myeloma (MM), a blood cancer of terminally differentiated, immunoglobulin-producing B-lymphocytes called plasma cells that remains incurable in the great majority of cases. We will consider bona fide myeloma CIN genes, methods for measuring CIN in myeloma cells, and novel approaches to CIN-targeted treatments of patients with myeloma. The new findings generate optimism that enhanced understanding of CIN will lead to the design and testing of new therapeutic strategies to overcome drug resistance in MM in the not-so-distant future.

Chromosomal Instability in Tumor Initiation and Development

“…107) might provide novel drug targets that could overcome the drug resistance associated with CIN, especially when combined with therapies that target known tumor suppression or oncogenic pathways or signal transduction in cancer patients. Some studies indicate that CIN modulates tumor heterogeneity in patients with myeloma and contributes to acquired drug resistance in multiple myeloma (108). As a result, targeting CIN upfront can be a potential approach to prevent genetic heterogeneity from occurring; new experimental model systems of CIN-dependent malignancy are needed for developing new therapies (108).…”

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

“…Decades of fundamental and clinical research have shown that CIN has tremendous implications in cancer development, progression, and clinical outcomes ( Figure 1). For example, CIN is associated with cellular transformation [9,50], tumor evolution and progression including intertumoral and intratumoral heterogeneity [51][52][53], metastasis [54][55][56], and the acquisition of drug resistance [57,58]. Thus, it is perhaps unsurprising that the presence of CIN is typically associated with worse patient outcomes [59][60][61][62].…”

“…This is especially relevant, as a protracted disease course inevitably leads to extensive genetic diversity within a CIN tumor cell population, such that the cells present in a late stage tumor are genetically disparate from those biopsied or removed at the time of primary surgery in early stage disease [155]. Furthermore, as CIN confers multidrug resistance [57,58], single agent strategies typically fail due to the ineffectiveness of the treatment across the entire tumor population and/or the adaptive nature of the cells exhibiting CIN. Thus, the accuracy of prognostic stratification will likely provide limited insight, as the diagnostic information is restricted to the region that is analyzed.…”

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

“…Advances in surgical techniques, cancer-specific therapies and small molecule inhibitors have contributed to survival and disease-free duration [1]. However, the development of multiple drug resistance (MDR) to first-line chemotherapeutic agents leaves few, if any, proven treatment options, and may signal a shift to palliative support rather than active therapy [2][3][4][5][6]. MDR can be inherent (prior to treatment) or acquired at any time after initial treatment responsiveness, with recrudescence as much as 20 years later [7,8].…”