Understanding Intratumor Heterogeneity and Evolution in NSCLC and Potential New Therapeutic Approach

Abstract

Advances in innovative technology, including next-generation sequencing, have allowed comprehensive genomic analysis and the elucidation of the genomic aspect of intratumor heterogeneity (ITH). Moreover, models of the evolution of the cancer genome have been proposed by integrating these analyses. Cancer has been considered to accumulate genetic abnormalities for clonal evolution in time and space, and these evolutionary patterns vary depending on the organs of primary sites. Selection pressure is an important determinant of such evolutionary patterns. With weak selection pressure, more diverse clones coexist, and heterogeneity increases. Heterogeneity is maximized when there is no selection pressure; in other words, neutral evolution occurs. Some types of cancer such as lung cancer evolve in conditions that have maintained close to neutral evolution and produce diverse variants. This ITH is a key factor contributing to the lethal outcome of cancer, therapeutic failure, and drug resistance. This factor reaffirms the complexity and subtle adaptability of cancer. It is expected that further understanding of ITH and cancer genome evolution will facilitate the development of new therapeutic strategies to overcome ITH.

Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers

“…The consistency of mutations across multiple sites, with complete concordance in the position and patterns of base-pair substitutions or indels, cannot be a coincidental phenomenon. Although discordance between two tumors was noted in mutations with an allele fraction <20%, this can be interpreted as tumor heterogeneity [14]. In general, cancers comprise populations of cells with various molecular and phenotypic features, a phenomenon termed intratumor heterogeneity [14,15].…”

“…Although discordance between two tumors was noted in mutations with an allele fraction <20%, this can be interpreted as tumor heterogeneity [14]. In general, cancers comprise populations of cells with various molecular and phenotypic features, a phenomenon termed intratumor heterogeneity [14,15]. This may bolster tumor adaptation, cancer progression and metastasis, and/or therapeutic failure through negative selection [14,16].…”

“…In general, cancers comprise populations of cells with various molecular and phenotypic features, a phenomenon termed intratumor heterogeneity [14,15]. This may bolster tumor adaptation, cancer progression and metastasis, and/or therapeutic failure through negative selection [14,16]. Conversely, a driver mutation triggers clonal expansion and is retained ubiquitously within the tumors of the same clone [16,17].…”

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

“…It is considered that 20,000 proteins are implicated and play key roles in cancer biology; however, today, a majority of these structural and regulatory classes of proteins appear to be undruggable. Alternatively, some identified targets have no drugs developed [23,29,30].…”

“…In this model, unlike the clonal evolution and stem cell theories, reversible molecular changes result in tumor heterogeneity. Inconsistent drug responses between cancer cells can be a result of diversification of epigenomic, transcriptomic, proteomic, metabolic, and functional states driven by tumor cell microenvironment changes [8,29,35,36]. One of the mechanisms of phenotypic change is via EMT, an evolutionarily conserved program of transdifferentiation.…”