Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures

Abstract

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.

Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

“…Future research should investigate the implications of the emerging plastic view of resistance (e.g. [35]) for adaptive therapy.…”

Modeling collaterally sensitive drug cycles: shaping heterogeneity to allow adaptive therapy

“…Given the importance of (epi-)mutation, and not just changing frequencies, it is uncertain on what timescales this is a fair assumption. [8] Another simplification we have made is to assume that there is no interaction between celltypes, something which has been shown in at least breast [35], lung [16] and pancreatic cancers [36]. However, we believe our cell classification structure is meaningful in that it reflects collateral sensitivity phenomena reasonably and the simplicity of the corresponding linear ODE system enables analytic study.…”

“…The evolution of resistance to initially effective therapies is one of the primary forces behind this phenomenon. This evolution is a complex phenomenon influenced by a variety of factors and their interactions [3,4,5], including genetic mutation and changed frequency of gene expression [6,7,8], drug efflux pumps on the cell membrane [9,10], tumor microenvironement [11] and so on. Despite the difficulty of elucidating these complicated mechanisms, a multitude of (epi)genetic factors may converge to evolve finite phenotypes.…”

Detection and Characterization of Musculoskeletal Cancer Using Whole-Body Magnetic Resonance Imaging

“…Compared with clinical assessments and bone tumor markers, radiologic methods for metastatic evaluations have multiple strengths and limitations (►Table 2). Radiologic strengths include 1 the ability to separately assess primary tumors, bone, nodal, and visceral disease spread, 2 their noninvasive nature, 3 documentation capability, 4 ability for wholebody tumor imaging coverage for many modalities, 5 resolution flexibility (submillimeter to subcentimeter), 6 ability to depict physiologic and molecular processes of the calcified bone, normal bone marrow, and bone marrow lesions, 7 ability to depict differences in phenotypes within and between lesions and patients, 8 and the ability to assess spatial heterogeneity of disease distribution and response.…”

“…CTs are well suited to assessing bone complications related to the presence of tumors, primarily pathologic fractures. 4,5 We have noted that CT scans can be helpful for clarifying the nature of lesions depicted on BS. Cross-sectional imaging, including CT, is needed to assess visceral involvement, as well as soft tissue extension of bone tumors that may be critical if they involve the spinal canal.…”