Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures (original) (raw)
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Advancements in rational drug design over the past decades have consistently produced new cancer therapies, but such treatments are inevitably countered through an adaptive process that fosters therapy resistance. Malignant cells achieve drug resistance through intrinsic and acquired mechanisms, rooted in genetic and non-genetic determinants. In particular, recent work has highlighted the role of intrinsic cellular heterogeneity in the emergence of transient drug-tolerant persister cells that survive drug treatment, as well as non-genetically driven cell plasticity toward stable resistance. However, these models do not account for the role of dose and treatment duration as extrinsic forces in eliciting cancer cell adaptation. Here, we show that these two components together drive the resistance of ovarian cancer cells to targeted therapy along a trajectory of cellular adaptation, that we denote the ‘resistance continuum’. We report that gradual dose exposure and prolonged treatment ...
Journal of Cell Communication and Signaling, 2017
The enthusiasm about successful novel therapeutic strategies in cancer is often quickly dampened by the development of drug resistance. This is true for targeted therapies using tyrosine kinase inhibitors for EGFR or BRAF mutant cancers, but is also an increasingly recognized problem for immunotherapies. One of the major obstacles of successful cancer therapy is tumor heterogeneity of genotypic and phenotypic features. Historically, drivers for drug resistance have been suspected and found on the genetic level, with mutations either being pre-existing in a subset of cancer cells or emerging de novo to mediate drug resistance. In contrast to that, our group and others identified a non-mutational adaptive response, resulting in a reversible, drug tolerant, slow cycling phenotype that precedes the emergence of permanent drug resistance and is triggered by prolonged drug exposure. More recently, studies described the importance of initially reversible transcriptional reprogramming for the development of acquired drug resistance, identified factors important for the survival of the slow cycling phenotype and investigated the relationship of mutational and non-mutational resistance mechanisms. However, the connection and relative importance of mutational and adaptive drug resistance in relation to the in vitro models at hand and the clinically observed response patterns remains poorly defined. In this review we focus on adaptive intrinsic phenotypic plasticity in cancer cells that leads to the drug tolerant slow cycling state, which eventually transitions to permanent resistance, and propose a general model based on current literature, to describe the development of acquired drug resistance.
Non-Darwinian dynamics in therapy-induced cancer drug resistance
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The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells.
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It is widely acknowledged that there is a need for molecular profiling in non-small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a...
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Drug resistance is a serious impediment in treating cancer. However, the mechanisms involved remain poorly understood. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that non-genetic mechanisms may also be important. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapy, as opposed to sustained monotherapy, appear more effective in attenuating it. Here, we iterate the confusion in understanding the phenomenon by which cancer cells evade drug response, and underscore the need to recognize the genetic/non-genetic duality of drug resistance in cancer. We discuss how ecological and evolutionary principles may help reconcile the duality, and may even offer new treatment strategies.
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Acquired drug resistance is a major limitation for successful treatment of cancer. Resistance emerges due to drug exclusion, drug metabolism and alteration of the drug target by mutation or overexpression. Depending on therapy, the type of cancer and its stage, one or several genetic or epigenetic alterations are necessary to confer resistance to treat- ment. The fundamental question is the
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Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.
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Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with EGFR or ALK tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MEK inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and FGFR inhibitors was active in an EGFR mutant resistant cancer with a novel mutation in FGFR3. Combined ALK and SRC inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further ...
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Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strat...