As the genomic classification of lung cancer continues to evolve and as the mechanisms of acquired resistance to targeted therapies become elucidated and more improved targetspecific drugs come. Mutations linked to immunotherapy resistance national. Tumor cells are tkisensitive or tkirefractory, exhibit. Mar 19, 2020 mechanisms underlying acquired resistance to pathway targeted drugs are being pursued largely through two basic strategies. Nov, 2019 the emergence of resistance mutations in patients with cancer who receive targeted therapies is an expected development that will require new diagnostic methods of identifying the mechanisms through which these alterations occur, according to fei dong, md, during the 2019 association for molecular pathology annual meeting. Targeted therapies have opened new perspectives in clinical oncology. Ptpn11 suppression is lethal to cells that are driven by activated rtks and prevents acquired resistance to targeted cancer drugs that results from rtk activation. Cancer copyright 2020 prior acquired resistance to.
Acquired resistance is a particular problem, as tumours not only become resistant to the drugs originally used to treat them, but may also become crossresistant to other drugs with different mechanisms of action. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti cancer medicine. Pdf mechanisms of acquired resistance to fibroblast. Acquired cancer resistance to combination immunotherapy from.
Cellautonomous and noncellautonomous mechanisms of hgfmet. Understanding mechanisms of late acquired cancer immunotherapy resistance is critical to improve outcomes. Mechanisms of resistance highlights examples of changes in the signaling network in response to inhibition of a signaling event and underscores. In vivo screen identifies drivers of antiandrogen resistance in prostate cancer. Investigating new mechanisms of acquired resistance to. Resistance to targeted drugs can be classified as intrinsic primary or acquired secondary and often relies on cellular. Kaist researchers identify mechanism that fuels a domino. Emerging insights of tumor heterogeneity and drug resistance. Acquired resistance to tyrosine kinase inhibitors targeting egfr mutations in patients with nonsmall cell lung cancer are leading to nextgeneration therapies equipped to circumvent the mutations that arise from initial treatment. In addition, new discoveries in mechanisms of drug resistance. Emergence of kras mutations and acquired resistance to.
Mechanisms of acquired resistance to fibroblast growth factor. Resistance can be intrinsic to a cancer cell already in place prior to. Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Ptpn11 is a central node in intrinsic and acquired resistance. Repeated tissue biopsy is important to explore resistance mechanisms, but it has limitations and risks. A growing body of evidence indicates that met, the. Cancer blockade of egfr and mek intercepts heterogeneous mechanisms of acquired resistance to antiegfr therapies in colorectal cancer sandra misale,1,2 sabrina arena,1,2 simona lamba,1,2 giulia siravegna,1,2 alice lallo,1,2 sebastijan hobor,2 mariangela russo,1,2 michela buscarino,2 luca lazzari,2,3 andrea sartorebianchi,4 katia bencardino,4 alessio amatu,4 calogero lauricella,5. Mapk pathway alterations correlate with poor survival and. Therefore, understanding resistance causing mechanisms is a critical challenge to improve the outcome of candidates for such treatment strategies.
In this issue of cancer research, finn and colleagues demonstrate that modeling acquired resistance to met tyrosine kinase inhibition in a met. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. The relatively new paradigm of rationally targeted cancer drug therapies has dramatically impacted the practice of medical oncology, with the discovery and development of personalized cancer medicines that produce remarkable clinical responses in a subset of patients with advanced systemic disease. Request pdf polytherapy and targeted cancer drug resistance a current. Downstream signaling is decreased upon addition of a targeted inhibitor. Purpose some gastric cancers harbor met gene amplifications that can be targeted by selective met inhibitors to achieve tumor responses, but resistance eventually develops. Pdf acquired resistance to egfr targeted therapy in non. Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy david k. Heterogeneous mechanisms were enabled to escape from luminal lineage and therapy. Therefore, a compelling challenge is to identify mechanisms underlying resistance and strategies to circumvent these hurdles.
Acquired resistance to targeted therapies in nsclc. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. Polytherapy and targeted cancer drug resistance request pdf. We need to distinguish between primary resistance, referring to patients who experience an immediate inefficacy of egfrtkis, and secondary or acquired resistance, which is usually defined as progression of the disease. Optimal treatment for the various mechanisms of acquired resistance is not yet clearly defined, except for the t790m mutation. In the first section of this study, crc cell lines that developed acquired resistance to antiegfr therapies were molecularly characterized. Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from her2 inhibition. The articles in this ccr focus provide insights into molecular mechanisms of resistance to targeted therapy. Common acquired resistance mechanisms include the selection of tumor cells with. Drug combinations to overcome treatment resistance. Savolitinib, a selective met inhibitor, is beneficial for treating patients with metdriven gastric cancer.
More than 30 years ago, they discovered that in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to overexpress abc transporters, he said. Tme mechanisms of resistance to targeted therapies. Loss of chd1 promotes heterogeneous mechanisms of resistance. Tumors develop resistance to all types of targeted therapy, including. Mechanisms of intrinsic and acquired resistance to kinase. Understanding how tumors acquire resistance to checkpoint inhibitors is critical, the study authors wrote, and may help guide the development of targeted therapies that could counteract resistance. Chd1 loss establishes a state of chromatin dysregulation and lineage plasticity. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. Pdf targeted therapies in cancer and mechanisms of resistance. Mechanisms of acquired resistance to targeted cancer therapies. Reviewmolecular mechanisms of acquired resistance to tyrosine kinase targeted therapy j rafael sierra 1,2, virna cepero and silvia giordano1 abstract in recent years, tyrosine kinases tks have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogen esis, and are therefore considered suitable. Drug resistance and combating drug resistance in cancer.
Helen creedon, adam byron, joanna main, larry hayward, teresa klinowska, valerie g. Patients with innate resistance have been found to contain brafv600e mutations, and. Exploring mechanisms of acquired resistance to her2 human epidermal growth factor receptor 2 targeted therapies in breast cancer. Resistance to kinase inhibitors and implications for therapeutic. Ptpn11 is a central node in intrinsic and acquired. The intrinsic resistance primarily serves as a guide to the choice of first line treatment. Clinical development of targeted and immune based anticancer. On the other hand, mechanisms of acquired resistance to pathway targeted drugs, such as the various clinically active kinase inhibitors, have been somewhat more straightforward to. Mechanisms of acquired drug resistance to lung cancer targeted therapy. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood 38. Treatment approaches for egfrinhibitorresistant patients with nonsmallcell lung cancer.
In this issue of cancer research, finn and colleagues demonstrate that modeling acquired resistance to met tyrosine kinase inhibition in a metamplified gastric cancer cell line by a single, high exposure of the targeted therapy reveals clinically relevant acquired resistant mechanisms, which may be more faithful and comprehensive than the ones. Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Lau and others published mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy find, read and cite all the research you need on. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Molecular mechanisms of tumor cell resistance to chemotherapy. Several studies unveiled gainoffunction mutations in theesr1 gene in.
One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Resistance to targeted therapies clinical cancer research. Resistance can be mediated either by genetic or nongenetic mechanisms. Innate and acquired resistance to antiegfr therapy egfri is a major limitation in the treatment of metastatic colorectal cancer mcrc. Targeted therapies mechanisms of resistance daniel gioeli. Here, we show for the first time that molecular alterations in most instances point mutations of kras are causally associated with the onset of acquired resistance to antiegfr treatment in colorectal cancers. Treatment approaches for egfrinhibitorresistant patients. The problem of resistance to therapy in cancer is multifaceted. The immune system includes several so called checkpoint proteins that keep immune responses from becoming too strong.
Leto and trusolino discuss the mechanisms of primary and acquired resistance to egfr targeted therapies in colorectal cancer. Acquired resistance to egfr targeted therapy in nonsmall. Intrinsic and acquired resistance to her2targeted therapies. Traditionally, mechanisms of tki resistance have been viewed under a dichotomous lens. However, as observed with all targeted therapies, resistance arises. Targeted therapies in cancer and mechanisms of resistance. Management of acquired resistance to egfr tkitargeted. Thus, like bacteria, cancer cells can adapt to therapeutic pressure by enhancing their mutability. Mar 20, 2017 mechanisms of resistance to targeted therapies. Other innovative targets besides er are urgently needed to prevent the development of a whack. Promise is seen in newer egfr tkis to overcome resistance. However, in almost an invariable fashion, cancers eventually regrow in the presence of the targeted therapy, a phenomenon referred to as acquired resistance. In the case of permitted digital reproduction, please credit the national cancer institute as the source and link to the original nci product using the original products title.
Reviewmolecular mechanisms of acquired resistance to. A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. We need to distinguish between primary resistance, referring to patients who experience an immediate inef. Different mechanisms of acquired resistance to firstgeneration and secondgeneration egfr tkis have been reported. Pdf mechanisms and potential therapies for acquired resistance to inhibitors targeting the raf or mek kinases in cancer. Mechanisms of tumor cell resistance to the current targeted. Cancer blockade of egfr and mek intercepts heterogeneous mechanisms of acquired resistance to antiegfr therapies in colorectal cancer sandra misale,1,2 sabrina arena,1,2 simona lamba,1,2 giulia siravegna,1,2 alice lallo,1,2. Detecting mechanisms of acquired resistance ar is crucial to finding novel therapies and improve patient outcomes. Pdf molecular mechanisms of acquired resistance to. A current challenge in cancer treatment is drug resistance. Mar 17, 2020 on the other hand, mechanisms of acquired resistance to pathway targeted drugs, such as the various clinically active kinase inhibitors, have been somewhat more straightforward to elucidate and.
Long before the era of broad tumor genomic characterization and the generalized interest in mechanism based targeted therapies for cancer, tamoxifen was proposed as a groundbreaking therapy. Acquired cancer resistance to combination immunotherapy. In this tumor type, there is no predictor of response to egfr antibodies, but clinical treatment takes advantage of the identification of several negative predictors of response, such as mutations of kras, braf, or. Cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. Mechanisms of acquired resistance to fibroblast growth. Mechanisms of acquired resistance to targeted cancer. Our findings identify ptpn11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Targeted therapies have revolutionized treatment of several different types of cancers.
Endocrine resistance will eventually develop in patients with erpositive breast cancer receiving endocrine therapy. Mechanisms of acquired resistance to savolitinib, a. Ros1 tyrosine kinase inhibitors tkis provide significant benefit in lung adenocarcinoma luad patients with ros1 fusions. Exploring mechanisms of acquired resistance to her2 human. Targeted therapies such as kinase inhibitors and monoclonal antibodies have dramatically altered cancer care in recent decades. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy article pdf available in molecular cancer 975. A more detailed understanding of the biology of egfrmutant nsclc and the mechanisms of resistance to targeted therapy mean that an era of treatment approaches based on rationally developed drugs or therapeutic strategies has begun. Feb 19, 2014 this study was designed to define the mechanisms of acquired resistance to egfr blockade in crc and to define pharmacological strategies to overcome acquired resistance to cetuximab and panitumumab. Increased lactate secretion by cancer cells sustains non. Drug resistance inevitably limits the efficacy of all targeted therapies including tyrosine kinase inhibitors tkis. Resistance to molecularly targeted therapies is a pervasive problem in the management of advanced cancers.
However, clinicians have observed a lack of response in a relevant percentage of patients and frequent relapse in patients who initially respond. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. Drug combinations to overcome treatment resistance national. Molecular mechanisms of acquired resistance to tyrosine. Adaptive mutability of colorectal cancers in response to. Second, acquired resistance occurs during the course of therapy when the cancer cell gains a selective advantage 55 56 57.
Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Prior acquired resistance to paclitaxel relays diverse egfr. However, resistance to such targeted therapies is an inevitable consequence of this. This volume explores the mechanisms of resistance to targeted therapeutics. One potential strategy proposed to overcome acquired resistance involves taking repeat tumor biopsies at the time of. Both clinical and experimental aspects of drug resistance in cancer are included.
The biggest hurdle to targeted cancer therapy is the inevitable. Strategies for monitoring and combating resistance to combination. Lau 1,2, laura jenkins, andrew weickhardt 1,2,3 1olivia newton john cancer research institute, heidelberg, victoria 3084, australia. Acquired resistance to egfr targeted therapy in nonsmall cell lung cancer. Two new studies show that mechanisms of acquired resistance to targeted therapy in lung cancer do not necessarily preexist in resistant subclones. Patients with innate resistance have been found to contain brafv600e. Dec 20, 2019 they found that human colorectal cancer cells treated with certain targeted therapies display a transient upregulation of errorprone dna polymerases and a reduction in their ability to repair dna damage. Although these targeted therapies have improved patient outcomes in several cancer types, resistance ultimately develops to these agents. Resistance to chemotherapy is believed to cause treatment failure in over 90% of patients with metastatic cancer, and resistant.
Experimentally, drug resistance is established in cell lines in vitro by repeated, continuous exposure to escalating concentrations of the drug. Prior acquired resistance to paclitaxel relays diverse. The cellular origins of drug resistance in cancer nature. Kaist researchers have identified mechanisms that relay prior acquired resistance to the firstline chemotherapy to the secondline targeted therapy, fueling a domino effect in cancer drug. Why are they so important to the future of oncology. Our findings identify ptpn11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer. We describe specific mechanisms of primary and acquired. Sep 24, 2018 understanding mechanisms of lateacquired cancer immunotherapy resistance is critical to improve outcomes. Mechanisms of innate and acquired resistance to antiegfr. Sep 11, 20 unlike resistance to traditional anticancer agents, the mechanisms of resistance to targeted therapies observed in vitro are generally found to correspond to those observed in vivo, which has allowed researchers to study the mechanisms closely and to begin to develop newer agents to outsmart cancer. The focus is on the cancer cell signaling network, although other mechanisms of resistance including target mutation, and new areas of study such as cancer stem cells are included. Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc.
The journal focuses on pharmacological aspects of drug resistance and its reversal, including drug design, drug delivery, drug distribution and cellular drug resistance, etc. Understanding the biological underpinnings of tki resistance is key to the successful development of future therapeutic strategies. Strategies for monitoring and combating resistance to. Thymidine kinase 1 loss confers trifluridine resistance. Downstream signaling is decreased upon addition of a. Acquired resistance to sorafenib is often encountered in hcc. Apr 21, 2017 targeted therapies such as kinase inhibitors and monoclonal antibodies have dramatically altered cancer care in recent decades. Blockade of egfr and mek intercepts heterogeneous mechanisms. While increasingly effective therapies have been developed, we are limited in our efforts toward cure by acquired resistance to therapy. One potential strategy proposed to overcome acquired resistance involves taking repeat tumor biopsies at the time of disease. Using resistance selection and smallscale pharmacological screens, we find that cancer cells with primary acquired resistance to the microtubulestabilizing drug paclitaxel often develop tolerance to epidermal growth factor receptortyrosine kinase inhibitors egfrtkis, leading to formation of more stable resistant cell populations. Although ras genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of egfri.