The influence of subclonal resistance mutations on targeted cancer therapy

Abstract

Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. It is becoming increasingly clear that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients.

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…Tumor heterogeneity and the impact of subclonal somatic mutations on the response to targeted cancer therapies have been frequently discussed in relation to various cancers. 57 Of interest, in a recent publication, there was evidence that low-frequency mutations in KRAS may cause resistance to anti-epidermal growth factor receptor therapy in colorectal cancer, even if mutant allele frequency was as low as 0.4% to 17%, 58 and similar reports were published for gefitinib resistance in lung cancer. 59,60 The authors discuss potential explanations, including amplification of the gene locus and the possibility of parallel evolution of distinct resistance mechanisms within different subclones of a tumor.…”

Aberrant Splicing in Cancer: Mediators of Malignant Progression through an Imperfect Splice Program Shift

“…Thus, to some extent, the splice shift is irreversible, conferring plastered features. Therefore, when considering tumor progression by the acquisition of new features and loss of previous features, as seen in several aggressive and resistant cancer types [48], this loop acts only straightforward in a vicious circle that repeats the same steps, but conferring new features. Thus, at the level of splicing factors and the splice program, it is not possible to say that a total reversion exists, but in the analyzed literature, splice program shifts have been described, in accordance with the dominance of the splicing factors that govern the splice program in many aggressive and poorly differentiated tumors [7,14,16,17,23,32,37,49].…”

Computational Errors and Biases in Short Read Next Generation Sequencing

“…It is very important to distinguish between crosscontamination calls and low level mutation, which is the aim in studies such as cancer somatic mutations (sub-clonal mutations) [152,224].…”