Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells

Abstract

Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a ‘persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit—and may even provide a latent reservoir of cells for—the emergence of heterogeneous drug-resistance mechanisms.

Epigenetics in Melanoma Development and Drug Resistance

“…Elevated EGFR and PDGFRβ levels have been shown to be reversible after discontinuing BRAF and MEK inhibitor treatment, while expression of EGFR or treatment with TGF-β resulted in a slow cycling drug-resistant phenotype [72]. This observation reflects findings by our group [73] and others [74,75] of reversible multidrug-tolerant slow-cycling state following stressors like drug treatment. Beside failure of BRAF inhibition, a recent study found that dynamic and recurrent non-genomic alterations following chronic BRAF inhibitor treatment also affect tumor immunity possibly resulting in cross resistance to anti PD-1 therapy [76].…”

“…A possible explanation for the discrepancy between the discussed studies in regards to the different strategies to target heterogenous slow cycling populations could be that the KDM5A high or KDM5B high cells are stringently selected subtypes of the slow cycling phenotype whereas IDTCs are characterized by multiple epigenetic modifiers, most likely including multiple subtypes that contribute to the same phenomenon. The dynamic signaling rewiring observed in the IDTC phenotype is reminiscent of the diverse drug resistance mechanisms that have been reported to emerge from slow cycling EGFR inhibitor addicted lung cancer cells [75], which suggests that an adaptive response as described for IDTCs in melanoma might be present in multiple cancer types. One key feature of all slow cycling drug-tolerant cell populations that emerge after 3-12 days of drug exposure is the reversibility upon drug withdrawal.…”

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

“…When CTCs from patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2 − ) breast cancer who developed metastatic multidrug-resistant disease were cultured in vitro, they maintained a discrete population of Her2 + and Her2 − cells that interconvert spontaneously with significant consequences for disease progression and drug response. Although the underlying mechanisms driving spontaneity in state switching were not elucidated, the study by Jordan et al (59) and several other studies in different types of cancer (60)(61)(62)(63) suggest that the phenomenon of state switching driven by nongenetic variability need not be restricted to bacterial "persisters" and may be fairly common in cancer. For example, cancer cells in a hybrid epithelial/mesenchymal state, when cultured, can give rise to epithelial and mesenchymal cells predominantly (64).…”

Tumor Evolution as a Therapeutic Target

“…Interestingly, these cells appear to be less sensitive to third-generation EGFR inhibitors (65). Moreover, Ramirez and colleagues demonstrated that multiple resistance mechanisms could emerge from a single drug-tolerant clone of PC9 cells sensitive to erlotinib (67), and drug sensitivity of drug-tolerant PC9 cells is restored by IGF1R inhibition (66). EGFR ECD mutations were shown by Van Emburgh and colleagues to emerge later in cfDNA when compared with RAS mutations and to be associated with longer progression-free survival in patients with metastatic CRC (68); this observation is consistent with a two-step progression model of de novo acquired resistance.…”