Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity. Tumors are composed of millions of cancer cells embedded in a microenvironment distorted by neoplastic changes. The startling heterogeneity of both cancer cells and cells composing the tumor microenvironment fuels disease progression and treatment resistance. Thus, better understanding of cellular, molecular, and spatial heterogeneity within tumors and the application of this knowledge for treatment design are essential for improving clinical outcomes. In this review we summarize sources of intratumor heterogeneity (ITH), methods to quantitatively assess ITH, and its clinical relevance. Although most of the points discussed are applicable to all types of cancers, some, such as spatial and microenvironmental heterogeneity, are more relevant to solid tumors, which represent our main focus.