CDK9 inhibitors in multiple myeloma: a review of progress and perspectives

Abstract

Currently, multiple myeloma is not yet considered a curable disease. Despite the recent advances in therapy, the average patient lifespan is still unsatisfactory. Recently, CDK9 inhibitors emerged as a suitable agent to overcome resistance and prolong survival in patients with poor diagnoses. Downregulation of c-MYC, XIAP, Mcl-1 and restoration of p53 tumor-suppressive functions seems to play a key role in achieving clinical response. The applicability of the first generation of CDK9 inhibitors was limited due to relatively high toxicity, but the introduction of novel, highly selective drugs, seems to reduce the effects of off-target inhibition. CDK9 inhibitors were able to induce dose-dependent cytotoxicity in Doxorubicin-resistant, Lenalidomide-resistant and Bortezomib-resistant cell lines. They seem to be effective in cell lines with unfavorable prognostic factors, such as p53 deletion, t(4; 14) and t(14; 16). In preclinical trials, the application of CDK9 inhibitors led to tumor cells apoptosis, tumor growth inhibition and tumor mass reduction. Synergistic effects between CDK9 inhibitors and either Venetoclax, Bortezomib, Lenalidomide or Erlotinib have been proven and are awaiting verification in clinical trials. Although conclusions should be drawn with due care, obtained reports suggest that including CDK9 inhibitors into the current drug regimen may turn out to be beneficial, especially in poor prognosis patients.