Group Behavior and Emergence of Cancer Drug Resistance

Abstract

Drug resistance is a major impediment in cancer. Although it is generally thought that acquired drug resistance is due to genetic mutations, emerging evidence indicates that nongenetic mechanisms also play an important role. Resistance emerges through a complex interplay of clonal groups within a heterogeneous tumor and the surrounding microenvironment. Traits such as phenotypic plasticity, intercellular communication, and adaptive stress response, act in concert to ensure survival of intermediate reversible phenotypes, until permanent, resistant clones can emerge. Understanding the role of group behavior, and the underlying nongenetic mechanisms, can lead to more efficacious treatment designs and minimize or delay emergence of resistance.

Keywords: drug resistance; evolutionary game theory; group behavior; lung cancer; nongenetic mechanism; phenotypic switching.

Fig. 1.. Overview of the tumor microenvironment.

(A) Tumor microenvironment is a small niche which includes the heterogenous population of tumor cells, immune cells, blood vessels and stroma cells composed of activated fibroblasts; (B) The tumor microenvironment comprises of tumor cells, fibroblast, immune cells and endothelial cells. In normal tissue, the stromal fibroblasts are in a resting state and create a growth suppressive microenvironment, whereas the cancer-associated fibroblasts (CAFs) can have a tumor promoting effect. The cooperative role of CAFs and cancer cells in tumor proliferation have been extensively studied in various tumor types and some of the key functions are mentioned here. Growth factors (Transforming growth factor beta, Platelet derived growth factor), Interleukins (Il-6) or tumor-derived microRNAs present in exosomes, can activate resting fibroblasts and transform them into CAFs [31, 35, 36]. Epigenetic reprogramming induced by Leukemia Inhibitory Factor (LIF) through Histone acetyltransferase and DNA methyl transferase activates JAK/STAT signaling which can induce transformation of resting fibroblasts [41]. CAFs support tumor proliferation by activating endothelial cells and inducing tumor angiogenesis [33], through secretion of Stromal-derived Factor (SDF), Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGFA) [114]. It facilitates immune suppression by inducing macrophage M2 polarization, Myeloid to MDSC differentiation, or T-cells suppression through secretory chemokines and growth factors, or by expression of T cell inhibitory membrane proteins PD-L1, PD-L2, or FAS ligand [32]. Interleukin secretion by CAFs help to maintain cancer stem cell population., whereas metalloproteases, Insulin Growth Factor, or Growth Differentiation Factor secretion, help in tumor invasion, metastasis and/or resistance to chemotherapy

Fig. 2.. Biochemical network frustrations leading to phenotypic plasticity and facilitating permanent resistance.

(A) Analogy between protein residue networks and biochemical networks. Cooperative network of attractive inter-residue contacts stabilizes protein folded states and leads to a single deep well in the folding free energy landscape. Frustration in the inter-residue contact network (red crosses) leads to multiple stable states in the conformational landscape, while high network frustration leads to partially unfolded or intrinsically disordered states with high conformational flexibility. (B) Analogous view of the biochemical network. Frustration associated with major hubs (large green circles) can lead to multi-stability with switching between these states. (C) Left: Model gene interaction network, where multiple gene expressions can enhance (green edges) or suppress (red edges) drug resistance, thus leading to frustration in the network. Middle: Model fitness landscape as function of two genotypes; surrogate for a real multi-dimensional fitness landscape. Path taken by the tumor to achieve permanent resistance is shown in red. Frustrations in gene interaction network lead to evolutionary bottlenecks towards acquiring permanent resistance (valleys in the landscape). Right: plot of fitness along the path towards permanent resistance. Non-genetic mechanisms such as phenotype switching can smoothen the fitness valleys along the path, allowing the tumor to traverse evolutionary bottlenecks and achieve permanent resistance faster and more efficiently.