Provided herein are methods for identifying a cancer patient at risk for resistance to an HDAC inhibitor therapy, comprising obtaining a tumor sample from the cancer patient detecting the presence of Testis-specific Y-encoded-like protein 5 (TSPYL5) expression in the sample quantifying a level of the TSPYL5 expression in the sample, wherein a high level of the TSPYL5 expression, relative to a defined expression threshold of the TSPYL5, correlates with resistance to the HDAC inhibitor therapy and applying the correlation to identify the cancer patient at risk for resistance to the HDAC inhibitor therapy. Also provided is a method for identifying a cancer patient with an increased likelihood of a positive clinical response to an HDAC inhibitor therapy comprising obtaining a tumor sample from the cancer patient detecting the presence of Testis-specific Y-encoded-like protein 5 (TSPYL5) expression in said sample quantifying a level of said TSPYL5 expression in said sample, wherein a low level of the TSPYL5 expression, relative to a defined expression threshold of the TSPYL5, identifies said cancer patient with an increased likelihood of a positive clinical response to said HDAC inhibitor therapy. Related methods and compositions are also provided.
