Abstract: The present invention relates to the use of one or more biomarkers to evaluate the likelihood that a CDK4 inhibitor would produce an anti-cancer effect in a subject. It is based, at least in part, on the discovery that cancer cells expressing ATRX prior to treatment are more likely to undergo cellular senescence in response to treatment with a CDK4 inhibitor. It is also based, at least in part, on the discovery that ATRX is phosphorylated in cancer cells that are not as responsive to CDK4 inhibitor therapy. Accordingly, in non-limiting embodiments, the present invention provides for methods, compositions, and kits for a companion diagnostic for CDK4 inhibitors, and in particular, to the use of ATRX expression as a biomarker for determining the likelihood that a cancer can be successfully and/or unsuccessfully treated by CDK4 inhibition.