Maiso Patricia, Huynh Daisy, Moschetta Michele, Sacco Antonio, Aljawai Yosra, Mishima Yuji, Asara John M, Roccaro Aldo M, Kimmelman Alec C, Ghobrial Irene M
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Cancer Res. 2015 May 15;75(10):2071-82. doi: 10.1158/0008-5472.CAN-14-3400. Epub 2015 Mar 13.
Drug resistance remains a major clinical challenge for cancer treatment. Multiple myeloma is an incurable plasma cell cancer selectively localized in the bone marrow. The main cause of resistance in myeloma is the minimal residual disease cells that are resistant to the original therapy, including bortezomib treatment and high-dose melphalan in stem cell transplant. In this study, we demonstrate that altered tumor cell metabolism is essential for the regulation of drug resistance in multiple myeloma cells. We show the unprecedented role of the metabolic phenotype in inducing drug resistance through LDHA and HIF1A in multiple myeloma, and that specific inhibition of LDHA and HIF1A can restore sensitivity to therapeutic agents such as bortezomib and can also inhibit tumor growth induced by altered metabolism. Knockdown of LDHA can restore sensitivity of bortezomib resistance cell lines while gain-of-function studies using LDHA or HIF1A induced resistance in bortezomib-sensitive cell lines. Taken together, these data suggest that HIF1A and LDHA are important targets for hypoxia-driven drug resistance. Novel drugs that regulate metabolic pathways in multiple myeloma, specifically targeting LDHA, can be beneficial to inhibit tumor growth and overcome drug resistance.
耐药性仍然是癌症治疗的一项主要临床挑战。多发性骨髓瘤是一种无法治愈的浆细胞癌，选择性地定位于骨髓。骨髓瘤耐药的主要原因是对初始治疗（包括硼替佐米治疗和干细胞移植中的大剂量美法仑）耐药的微小残留病细胞。在本研究中，我们证明肿瘤细胞代谢改变对于多发性骨髓瘤细胞耐药性的调节至关重要。我们展示了代谢表型在多发性骨髓瘤中通过乳酸脱氢酶A（LDHA）和缺氧诱导因子1α（HIF1A）诱导耐药性方面前所未有的作用，并且特异性抑制LDHA和HIF1A可恢复对硼替佐米等治疗药物的敏感性，还能抑制由代谢改变诱导的肿瘤生长。敲低LDHA可恢复硼替佐米耐药细胞系的敏感性，而使用LDHA或HIF1A的功能获得性研究在硼替佐米敏感细胞系中诱导了耐药性。综上所述，这些数据表明HIF1A和LDHA是缺氧驱动的耐药性的重要靶点。调节多发性骨髓瘤代谢途径、特别是靶向LDHA的新型药物可能有利于抑制肿瘤生长并克服耐药性。
