Tumor Plasticity Driven by Spatial Micro-heterogeneity in the Tumor Microenvironment Contributes to Therapy Resistance

Abstract

Metastases account for over 90% of tumor related deaths. The classic anticancer inhibitors of cellular proliferation are also cytotoxic to host cells thus limiting effective doses and invariably leading to the development of drug resistance. Recent literature demonstrate some tumors harbor mutations like the EGFR-activating mutations in lung cancer or the BRAF V600E mutation in melanoma that can be targeted with specific inhibitors with promising clinical outcomes [1,2]. Even in such cases therapy is not guaranteed for all patients as tumors cease to respond after several rounds of drug treatment either because the tumor acquires resistance due to new mutations that bypass the blocked pathway or because resistant low-frequency sub clones become dominant. The fact that no treatment eliminates all tumor cells even though the re-emerging tumors are still sensitive to the treating drugs suggests that a fraction of the tumor cells are able to evade treatment through mechanisms as yet unclear. Factors contributing to therapy resistance include intra-tumor heterogeneity (genetic and phenotypic), tumor plasticity and spatial heterogeneity in the tumor microenvironment. Genetic intra-tumor heterogeneity arises from accumulating tumor mutations as tumor progresses. Most of the mutations, as in normal evolution, would be expected to be neutral or deleterious to the tumor cell. Some mutations however confer survival advantages as in the examples above [1,2], while other mutations may confer resistance to particular treatments. The EGFR T790M mutation for example confers resistance to EGFR tyrosine kinase inhibitors [3]. Establishing tumor mutation profiles enables better targeting of treatments.