Targeting Cell Survival Pathways To Enhance Response To Chemotherapy

Book Description :

Targeting Cell Survival Pathways to Enhance Response to Chemotherapy encompasses recently developed molecular targeting agents and approaches that suppress cell survival signaling. Cell survival signaling attenuates the effectiveness of conventional chemotherapy and numerous mechanisms have been described, and continue to be described, which contribute to cell survival in the face of chemotherapy treatment. Key pathways leading to chemoresistance emanate from growth factor receptors, PI3K, STAT3, anti-apoptotic Bcl-2 family members, autophagy, and the DNA damage response pathway. New advances have underscored the potential of targeting each of these cell survival mechanisms to improve responsiveness to chemotherapy. This book reviews these recent advances and provides a foundational background and hints of new opportunities for basic, translational, and clinical investigators focused on improving therapeutic responses to chemotherapy. Presents cutting-edge agents and approaches with proved success in different model systems that can be translated to a different type of cancer Brings updated information to be used to propose new clinical trials investigating innovative strategies for improving responses to chemotherapy Provides mechanistic details to help guide the design of laboratory studies associated with clinical trials

Book Description :

Targeting Cell Survival Pathways to Enhance Response to Chemotherapy encompasses recently developed molecular targeting agents and approaches that suppress cell survival signaling. Cell survival signaling attenuates the effectiveness of conventional chemotherapy and numerous mechanisms have been described, and continue to be described, which contribute to cell survival in the face of chemotherapy treatment. Key pathways leading to chemoresistance emanate from growth factor receptors, PI3K, STAT3, anti-apoptotic Bcl-2 family members, autophagy, and the DNA damage response pathway. New advances have underscored the potential of targeting each of these cell survival mechanisms to improve responsiveness to chemotherapy. This book reviews these recent advances and provides a foundational background and hints of new opportunities for basic, translational, and clinical investigators focused on improving therapeutic responses to chemotherapy. Presents cutting-edge agents and approaches with proved success in different model systems that can be translated to a different type of cancer Brings updated information to be used to propose new clinical trials investigating innovative strategies for improving responses to chemotherapy Provides mechanistic details to help guide the design of laboratory studies associated with clinical trials

Book Description :

This volume examines in detail the role of chronic inflammatory processes in the development of several types of cancer. Leading experts describe the latest results of molecular and cellular research on infection, cancer-related inflammation and tumorigenesis. Further, the clinical significance of these findings in preventing cancer progression and approaches to treating the diseases are discussed. Individual chapters cover cancer of the lung, colon, breast, brain, head and neck, pancreas, prostate, bladder, kidney, liver, cervix and skin as well as gastric cancer, sarcoma, lymphoma, leukemia and multiple myeloma.

Book Description :

Combination therapy is preferred over monotherapy to treat cancer as it can show better therapeutic outcomes and also delay the onset of resistance by targeting multiple cell-survival pathways in cancer cells. Rationally developed combinations with monoclonal antibodies and small molecule drugs in the form of antibody-drug conjugates or antibody nanoparticle conjugates allow us to take advantage of the cellular targeting of the potent cytotoxic agents, thereby widening the scope for dose reduction while maintaining the required therapeutic response. This can in turn improve patient tolerability by reducing the off target toxicities. For the therapy of ErbB2 positive breast cancer, the monoclonal antibody, Trastuzumab, is the FDA approved therapy. The receptor tyrosine kinase, ErbB2 is a viable target in 20-25 % breast cancer patients due to its overexpression. Its degradation is associated with slower progression of the disease and increased survival times. While the monoclonal antibody Trastuzumab (HerceptinTM) is the first line therapy in such patients, monotherapy with Trastuzumab has shown little benefit and therefore must be given with chemotherapeutic agents. Such combinations also help in delaying the development of resistance to Trastuzumab, since multiple cellular pathways can be targeted simultaneously. ErbB2 is a client protein of heat shock protein 90 and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of HSP90. Previous work in our lab has demonstrated strong synergy of action between 17-AAG and a model cytotoxic agent doxorubicin. In order to further improve the efficacy of the therapy, our goal was to replace doxorubicin with a more potent, clinically relevant agent paclitaxel (PTX), which has been shown to have strong synergistic antitumor effect with 17-AAG in ErbB2-driven breast cancers. Since synergy of such therapy is often sequence and dose ratio specific, co-delivery of the drugs via the same vehicle is desirable as well as beneficial. For this purpose, polymeric micelles prepared from a biodegradable block copolymer were chose. Polypeptides have an inherent property to assemble into supramolecular structures in solution. The formation of supramolecular structures is a controlled and organized process that depends by and large on the nature of the polypeptide and conditions of the solvent it is exposed to. Formation of amphiphilic copolymers based on such polypeptides can allow for tailoring the assembly process to a predefined nanoscale supramolecular structure, which can then be used as drug delivery vehicles. The overall process of self-assembly of such amphiphilic copolymers can then be regarded as a complex phenomenon of structural organization that is governed by the nature of constituent hydrophilic and hydrophobic blocks, their relative lengths, as well as properties of the solvent-phobic block that is the driving force for self-assembly. The inherent biocompatibility and biodegradability of polypeptides is of additional advantage for their biological applications. For the purpose of the current study, amphiphilic block copolymer with following composition was chosen: polyethylene glycol (PEG) as the hydrophilic, stealth imparting block and polyleucine (PLeu) as the hydrophobic part and the initiator of micelle formation in aqueous environment. The variables explored in the current study were altering the ratio of lengths of constituent blocks as well as chirality of PLeu block and the temperature of solvent used for preparation of micelles via the film rehydration method. The impact of all these variables on the thermodynamic stability as well as type of secondary structures formed and the influence of these attributes on the ability of the micelles to encapsulate a combination of hydrophobic drugs into their core are also described. Dual drug-loaded micelles thus prepared could load 17-AAG and PTX in a ratio 2:1 by weight. The formulation showed a high level of synergy on BT-474 cells that express a high amount of ErbB2 while the synergy was negligible in ErbB2low MCF-7 cells. The strong synergy also observed when the formulation was tested in an orthotopic breast cancer mouse model developed using ErbB2 overexpressing BT-474 cells, and an arrest in the growth of tumors in animals treated with dual drug-loaded micelles was observed, while both 17-AAG and PTX were used at sub therapeutic doses of 10 mg and 5 mg equivalents per kg body weight. The lower doses also helped avoid toxicity associated with the therapy. We also show the importance of simultaneously delivering the two drugs via a single carrier system as opposed to cocktail of individual drug-loaded micelles administered at equivalent doses, which has a better therapeutic outcome than the cocktail therapy. These combination drug-loaded micelles were developed as a platform for chemotherapy with Trast. The triple therapeutic system of Trast with combination drug-loaded micelles containing 17-AAG and PTX exhibited an even stronger anticancer effect, with complete regression of tumors at the end of treatment, which reached a palpable size again after day 45 with much slower progression than other treatment controls. Pancreatic cancer (PC) is one of the most lethal malignancies, due to aggressive tumorigenicity, early metastasis and development of drug resistance to standard care chemotherapy. Since its approval in 1997, Gemcitabine (Gem) has been the first-line treatment for advanced disease. However, there is no standard second-line therapy after Gem failure. FOLFIRINOX, a combination of four agents, folinic acid, fluorouracil, irinotecan and oxaliplatin was approved by the FDA in 2010. The rationale for this combination was based on these drugs having a different mechanism of action, and, more importantly, non-overlapping toxicities. In cases that could tolerate FOLFIRINOX, an overall improvement in the survival times as well as quality of life was noted. However, even the toxicities are non-overlapping, the cumulative toxicity profile for FOLFIRINOX can become the dose limiting factor. In the first trial itself, 50.8% of the patients needed dose adjustment. The common toxicities observed with FOLFIRINOX include Febrile neutropenia, Thrombocytopenic bleeding, ≥ grade 3 platelets, Grade 2 persistent neurotoxicity, Grade 3 persistent neurotoxicity OR Grade 4 neurotoxicity and many more non-hematological toxicities. Most of the toxicities are severe enough to require discontinuation of the treatment or switching to lower doses or alternative agents. The combination of Gem with Cisplatin (CDDP) has been explored in clinical trials for metastatic disease. As a part of FOLFIRINOX, platinum compounds showed significant efficacy. Cisplatin acts by damaging the DNA. It is known to

Book Description :

One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

Book Description :

This book is devoted to innovative medicine, comprising the proceedings of the Uehara Memorial Foundation Symposium 2014. It remains extremely rare for the findings of basic research to be developed into clinical applications, and it takes a long time for the process to be achieved. The task of advancing the development of basic research into clinical reality lies with translational science, yet the field seems to struggle to find a way to move forward. To create innovative medical technology, many steps need to be taken: development and analysis of optimal animal models of human diseases, elucidation of genomic and epidemiological data, and establishment of “proof of concept”. There is also considerable demand for progress in drug research, new surgical procedures, and new clinical devices and equipment. While the original research target may be rare diseases, it is also important to apply those findings more broadly to common diseases. The book covers a wide range of topics and is organized into three complementary parts. The first part is basic research for innovative medicine, the second is translational research for innovative medicine, and the third is new technology for innovative medicine. This book helps to understand innovative medicine and to make progress in its realization.

Book Description :

New Targeting in The Reversal of Resistant Glioblastomas discusses alternative treatment strategies that not only target tumor cells but also target the tumor microenvironment, metabolic pathways and interaction of cytokines in tumor cells. The current treatment for primary and recurrent glioblastomas is failing because clinicians are not considering the effect of bone marrow derived cells to the development of resistance to clinically practiced therapies. This book helps readers rethink treatment strategies to successfully fight glioblastomas. It is a valuable resource for cancer researchers, clinicians, graduate students and other members of the biomedical field. Explains the effect of bone marrow derived cells on the development of resistance to clinically practiced therapies Provides information on the availability of alternate therapies for recurrent glioblastoma when standard practices have failed Discusses targeting tumor microenvironment using available FDA approved drugs as an alternative treatment strategy for glioblastoma

Book Description :

With the explosion of information on autophagy in cancer, this is an opportune time to speed the efforts to translate our current knowledge about autophagy regulation into better understanding of its role in cancer. This book will cover the latest advances in this area from the basics, such as the molecular machinery for autophagy induction and regulation, up to the current areas of interest such as modulation of autophagy and drug discovery for cancer prevention and treatment. The text will include an explanation on how autophagy can function in both oncogenesis and tumor suppression and a description of its function in tumor development and tumor suppression through its roles in cell survival, cell death, cell growth as well as its influences on inflammation, immunity, DNA damage, oxidative stress, tumor microenvironment, etc. The remaining chapters will cover topics on autophagy and cancer therapy. These pages will serve as a description on how the pro-survival function of autophagy may help cancer cells resist chemotherapy and radiation treatment as well as how the pro-death functions of autophagy may enhance cell death in response to cancer therapy, and how to target autophagy for cancer prevention and therapy − what to target and how to target it. ​

Book Description :

Nanopharmaceuticals reviews advances in the drug delivery field via nanovehicles or nanocarriers that offer benefits like targeted therapy and serves as a single dose magic bullet for multiple drug delivery with improved drug efficiency at a lower dose, transportation of the drug across physiological barriers as well as reduced drug-related toxicity. The chapters are written by a diverse group of international researchers from industry and academia. The series Expectations and Realities of Multifunctional Drug Delivery Systems examines the fabrication, optimization, biological aspects, regulatory and clinical success of wide range of drug delivery carriers. This series reviews multifunctionality and applications of drug delivery systems, industrial trends, regulatory challenges and in vivo success stories. Throughout the volumes discussions on diverse aspects of drug delivery carriers, such as clinical, engineering, and regulatory, facilitate insight sharing across expertise area and form a link for collaborations between industry-academic scientists and clinical researchers. Expectations and Realities of Multifunctional Drug Delivery Systems connects formulation scientists, regulatory experts, engineers, clinical experts and regulatory stake holders. The wide scope of the book ensures it as a valuable reference resource for researchers in both academia and the pharmaceutical industry who want to learn more about drug delivery systems. Other volumes in the Expectations and Realities of Multifunctional Drug Delivery Systems book series: Delivery of Drugs, Volume 2, 9780128177761 Drug Delivery Trends, Volume 3, 9780128178706 Drug Delivery Aspects, Volume 4, 9780128212226 Encompasses functional aspects of nanocarriers Discusses Intellectual Property landscapes of micro-nano drug carriers Contains in-depth investigation of specific aspects of drug delivery systems

Book Description :

Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies brings current knowledge from an international team of experts on the science and clinical management of glioblastoma chemoresistance. The book discusses topics such as molecular mechanisms of chemoresistance, experimental models to study chemoresistance, chemoresistance to drugs other than Temozolomide, and specific strategies to reverse chemoresistance. Additionally, it encompasses information on how to mitigate chemoresistance by targeted enhancement of p53 function. This book is a valuable resource for cancer researchers, oncologists, neuro-oncologists and other members of the biomedical field. Glioblastoma (GBM) is the most invasive and malignant primary brain tumor in humans with poor survival after diagnosis, therefore it is imperative that molecular and cellular mechanisms behind therapy resistant GBM cells, as well as the therapeutic strategies available to counter the resistance are comprehensively understood. Provides comprehensive, core knowledge related to the entire discipline of glioblastoma chemoresistance, from its many etiological mechanisms, to specific strategies to reverse resistance Presents current information from an international team of experts on the basic science, pre-clinical research, and clinical management of glioblastoma chemoresistance Discusses molecular and cellular mechanisms behind therapy resistant glioblastoma cells, as well as the therapeutic strategies available to counter this resistance

Book Description :

As our understanding of apoptotic pathway expands, we are coming to realize the great potential of utilizing this pathway to treat diseases such as cancer. The book attempts to review, summarize, and speculate on the apoptotic pathways, how are they regulated and how targeted therapies are being used to treat a wide variety of diseases. Special emphasis is placed on cancer since new treatments either being developed or currently in the clinical setting are showing great promise to increase survival rates for cancer patients. Chapters will address the biology behind regulating the apoptotic pathways and what goes wrong in disease states whereas other chapters will concentrate on new therapies targeting apoptotic pathways. The reader by the end of the book should have greater insight into the understanding and utilization of apoptotic pathways to fight diseases such as cancer.

Book Description :

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. Explains the biology of ALK RTK, focusing on its tissue expression, structure and functionality Presents an overview of current treatments and the benefits of ALK TKI in lung and other cancer types, such as ALCL, neuroblastoma and inflammatory myofibroblastic tumor Encompasses information on systemic treatments other than TKI, including chemotherapy, immunotherapy and antiangiogenic agents in ALK-driven NSCLC

Book Description :

Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies

Book Description :

Overcoming Ovarian Cancer Chemoresistance presents non-overlapping review chapters that discuss the state of the field in overcoming chemoresistance of ovarian cancer and treatment options before and following recurrence, considering the genetic makeup of the ovarian cancer patient and her tumor. With the uptake of both germline and somatic gene testing, clinicians can obtain a more comprehensive understanding of ovarian tumors and this book provides information to link the genetic makeup of a tumor (or patient) with the best available treatment. The book discusses topics such as strategies to fight chemo-resistance in ovarian cancer, circulating DNA as a monitor of response, BRCA mutations, ovarian cancer stem cells, immunotherapy and vaccines. Additionally, it brings a list of promising agents at clinical and pre-clinical stage that will impact the treatment in the near future. This book is a valuable source for cancer researchers, oncologists and several members of biomedical field who need to understand how to battle chemoresistance in ovarian cancer. Provides a comprehensive view of both biological and genetic determinants of resistance, as well as technical approaches to monitor response Discusses genetic reversions as a unique alteration and a new field of study Includes a chapter on upcoming and promising agents that are in the pre-clinical and early clinical space, to set the stage for future directions in the field

Book Description :

pH Interfering Agents as Chemosensitizers In Cancer Therapy, Volume Thirteen, provides a detailed overview of the chemosensitizers for the treatment of cancer spanning from biochemical and structural features to pharmacology and drug-design, including technological applications. The book is structured with innovative outlines and a distinction between experimental and clinical results. The continuous discovery and assessment of the role played by old/new synthetic drugs, natural compounds and technological applications has led to the urgent need of classification in terms of biological activity, mechanism of action, clinical outcomes, cancer cell lines sensible to the treatment, and potentialities to better orient research in this field. Moreover, all the aspects relevant for medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, and molecular modeling studies) are strictly considered. Presents a broad view of the topic according to a medicinal chemistry-based approach beyond syntheses and biological assays, focusing on SAR studies, chemoinformatic, drug targeting and molecular modeling Explains the mechanism of action of the chemosensitizers by means of schemes and figures to facilitate comprehension Discusses novel targets to explore new possibilities that enhance research in the field

Book Description :

Novel Therapies in Head and Neck Cancer: Beyond the Horizon, Volume Twelve, provides a high-level synthesis of the latest treatments and outcomes relating to head and neck cancer. Chemotherapy and immunotherapy for those cancer types are rapidly evolving, and an updated source based on the expertise of internationally renowned researchers is necessary. This book discusses the outcome of recent trials using chemotherapy, novel approaches for HPV+ SCCA, cases in which immunotherapy is more likely to be successful, and precision medicine based on target therapies. Additionally, new approaches for rare diseases in head and neck and novel drug delivery platforms are presented. This book will be a very useful source so that students, scientists and clinicians who can be facile with the data, build on what is known, and continue to offer cutting-edge, validated therapies to all patients. Covers new chemotherapy trials, specifically on HPV and non-HPV related cancer types Discusses the application of immunotherapy to treat rare types of head and neck cancer Presents updated information on targeted therapies, specifically focusing on skin cancer in the region

Book Description :

Epigenetic Regulation in Overcoming Chemoresistance, Volume 19, explains how epigenetic agents can enhance the chemotherapy sensitivity of diverse types of cancers. The book provides a comprehensive delineation and the recent development of the scientific studies on the epigenetic regulation in enhancing chemo-sensitivity. In addition, it discusses several topics such as DNA methyltransferase inhibitors (DNMTi), Histone deacetylases inhibitors (HDACi), Histone lysine demethylases inhibitors (HDMi), Histone lysine methyltransferases inhibitors (HMTi) and drugs regulating the microRNA, long non-coding RNA (lncRNA) or RNA methylation. Finally, recent and future developments of the field of epigenetic regulation are explored. This is a valuable resource for cancer researchers, clinicians, graduate students and several members of biomedical field who are interested in learning about epigenetic regulation methods to reverse chemo-resistance in cancers. Presents detailed diagrams of the mechanisms of epigenetic regulation for easy consult Encompasses multiple clinical trial summary diagrams to help readers quickly and clearly get information from clinical trials Provides future perspectives in each section to inspire readers to use epigenetic regulation to overcome chemo-resistance

Book Description :

Drug Resistance in Colorectal Cancer: Molecular Mechanisms and Therapeutic Strategies, Volume Eight, summarizes the molecular mechanisms of drug resistance in colorectal cancer, along with the most up-to-date therapeutic strategies available. The book discusses reasons why colorectal tumors become refractory during the progression of the disease, but also explains how drug resistance occurs during chemotherapy. In addition, users will find the current therapeutic strategies used by clinicians in their practice in treating colorectal cancer. The combination of conventional anticancer drugs with chemotherapy-sensitizing agents plays a pivotal role in improving the outcome of colorectal cancer patients, in particular those with drug-resistant cancer cells. From a clinical point-of-view, the content of this book provides clinicians with updated therapeutic strategies for a better choice of drugs for drug-resistant colorectal cancer patients. It will be a valuable source for cancer researchers, oncologists and several members of biomedical field who are dedicated to better treat patients with colorectal cancer. Presents a systemic summary of molecular mechanisms for a quick and in-depth understanding Updates current trends in the field with pioneering information on drug resistance Encompasses both basic and clinical approaches for a better understanding of unsolved problems from a holistic point-of-view

Book Description :

Overcoming Drug Resistance in Gynecologic Cancers provides up-to-date information related to important gynecologic cancers and focuses on mechanisms of drug resistance, genetics, signaling, immunology, health disparities, nanotechnology, economic considerations and financial impacts. The book covers not only drug resistance but also important means to reverse resistance both in the laboratory and clinic. The book discusses topics such as lifestyle, nutrition and risk of gynecologic cancers, the financial impact of drug resistance, chemosensitizing agents and targeted therapies in cervical, endometrial and ovarian cancer, immunotherapy to overcome drug resistance, and genetic polymorphisms in gynecologic cancers. Additionally, it discusses ethnic and racial health disparity perspectives and future developments in chemosensitizing activities to reverse drug resistance in gynecologic cancers. It is a valuable resource for cancer researchers, oncologists, clinicians and other biomedical field members who are interested in new approaches to improve chemotherapy outcome in patients with gynecologic cancers. Provides a comprehensive resource with all the details needed for readers to understand and follow information Encompasses schematics, diagrams and flow charts in all chapters to help readers easily follow critical information Presents tables and figures especially developed to summarize the information with appropriate statistical rigor and to show details of clinical specimens such as pathological, radiological characteristics, and/or laboratory biomarkers

Book Description :

Overcoming Resistance to EGFR Inhibitors in EGFR Mutant NSCLC presents updated information on how EGFR mutant lung cancers evolve to evade EGFR inhibitors, clinical strategies that identify these mechanisms, and how to implement newer therapeutic strategies to combat resistance and improve patient survival. As resistance to EGFR inhibitors is often through re-activation of MEK/ERK and PI3K pathways, or through loss of cell death responses, there is much overlap with resistance to targeted therapies in other paradigms, such as BRAF inhibitors in BRAF mutant melanoma, and HER2 inhibitors in HER2 amplified breast cancer. This book is a valuable resource for cancer researchers, clinicians, graduate students and other members of the biomedical field who are interested in promising treatments for lung cancer. Presents historical context on how NSCLC and SCLC has been treated, with an emphasis on NSCLC and how the concept of EGFR inhibitors has been implemented Discusses critical resistant mechanisms seen in the clinic to 1st, 2nd and 3rd generation EGFR inhibitors Encompasses the current state of affairs in clinical trials to address resistance