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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Given the DDRs crucial role in maintaining genomic integrity, any defects in the process can lead to tumorigenesis. The most common defect is loss of the G1 cell-cycle checkpoint which allows cells to enter the cell-cycle unchecked. Paradoxically, these DDR defects cause cancer cells to become more reliant on the remaining intact repair processes to avoid catastrophic levels of genomic instability that would lead to apoptosis. This scenario is analogous to “oncogene addiction” which leads cancer cells to become heavily reliant on other signaling kinases (see Chapter 6). Another factor is that cancer cells with a high level of oncogenic alterations and an enhanced proliferation rate have to cope with dividing more often in the presence of DNA damage which can lead to higher levels of RS compared to healthy cells. Therefore, inhibition of the key DNA-repair proteins has been an important area of study, not just for the development of laboratory tools to dissect and study the DNA-repair networks but also to produce potential anticancer therapy strategies.
Adaptive Resistance Mechanisms in EGFR Mutant NSCLC
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Mariacarmela Santarpia, Niki Karachaliou, Martyna Filipska, Clara Mayo-de-las-Casas, Chiara Lazzari, Maria González-Cao, Rafael Rosell
Adaptive resistance can occur early during initial treatment with targeted therapies (Rosell et al., 2013). Pharmacological inhibition of several pathways of “oncogene addiction” is associated with feedback activation of a distinct signaling pathway leading to cell survival and residual disease, thereby limiting the effectiveness of drug treatment. Adaptive resistance can lead a small subpopulation of EGFR mutant lung cancer cells to survive despite EGFR inhibition and eventually develop acquired resistance. A variety of feedback mechanisms have been described in patients with activating EGFR mutations receiving different classes of EGFR TKIs. The characterization of the mechanisms involved in adaptive resistance can shed light on the dynamic genomic changes that oncogene-addicted cells undergo immediately after exposure to the selective pressure of targeted agents and provide rationale for upfront combinatorial therapeutic strategies to improve the limited efficacy of EGFR TKI monotherapy.
Tumor Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
The concept of “oncogene addiction” or “Achilles Heel” in cancer was proposed by I. B. Weinstein in the year 2002 (30). As discussed above, cancer cells produce their own ligands and also overexpress the receptors for these ligands, which in turn confer on cancer cells self sufficiency in growth signaling for their own survival. All cancer cells overexpress many of the signaling pathways that normal cells do not. Interestingly, it has been noted that blocking of any one of such signaling pathways in cancer can induce apoptosis, rather than a need to block several or all of them together. The first convincing example of this comes from the antibody trastuzumab (herceptin), which specifically targets the membraneassociated receptor tyrosine kinase Her-2 in breast cancers. Twenty to thirty percent of breast cancer cells over-expressing this receptor at their cell surface induce apoptosis upon blocking by this specific antibody. A second example is imatinib or gleevec, which specifically blocks the tyrosine kinase domain of BCR-ABL protein in leukemia. It is very effective in killing the leukemic cells and reducing the tumor burden in patients. Therefore, it has been proposed that cancer cells become “addicted” to the oncogenes or the oncogenic pathways. Therefore, blocking one oncogenic pathway could induce apoptosis in the cells that overexpress it. An oncogenic pathway may play a more essential role in cancer cells for their survival than the same pathway does in normal cells. Evidence of this strongly supports the idea of “mechanism-based chemotherapy” in cancer, that is, differentially killing cancer cells by blocking an oncogenic pathway without affecting the other normal cells in the body.
A prospective, multicenter, noninterventional study of decision factors in the first-line treatment of metastatic non–small cell lung cancer
Published in Acta Oncologica, 2022
Anne Sibille, Frederique Bustin, Luciano Carestia, Gaetan Catala, Christophe Compère, Kristof Cuppens, Benoit Colinet, Stephanie Coulon, Nele De Brucker, Lore Decoster, Lynn Decoster, Ingel Demedts, Sofie Derijcke, Koen Deschepper, Danny Galdermans, Annelies Janssens, Sebahat Ocak, Christel Oyen, Karin Pat, Thierry Pieters, Vincent Pruniau, Veerle Surmont, Saar Vandekeere, Johan Vansteenkiste
The treatment of metastatic non–small cell lung cancer (NSCLC) has evolved rapidly in recent years. For patients with nonsquamous cell carcinoma with oncogene addiction, targeted therapies are the preferred treatment, whereas immunotherapy (IT) has revolutionized treatment options for those without oncogene addiction and those with squamous cell carcinoma. IT treatment options, with or without chemotherapy (CT) are based primarily on expression levels of programmed death ligand 1 (PD-L1) [1]. These rapidly evolving treatment options and the molecular pathology testing required for optimal patient selection can be difficult to implement into daily practice, with technical (i.e., type of diagnostic test, expertise of the pathologist interpreting the results, and turnaround time) and reimbursement issues (i.e., treatment reimbursed without diagnostic test reimbursement) compromising PD-L1 testing. Real-world prescription data can serve as a tool for identifying such barriers to the implementation of optimal treatment. We therefore conducted a cross-sectional study to investigate the relationship between patient, tumor and treatment site characteristics, and systemic treatment choices for patients with untreated, stage IV NSCLC in the public health care system in Belgium with the aim of establishing a better understanding of the characteristics that impact real-life treatment decisions (NCT03959137; VEAP7678).
MYC, MYCL, and MYCN as therapeutic targets in lung cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Daniel Massó-Vallés, Marie-Eve Beaulieu, Laura Soucek
The relentless signaling through Myc by cancer cells is associated to its mutation, amplification or simply stabilization by upstream oncogenic signals. While it is clear that Myc is important for lung cancer pathogenesis, it might not be sufficient alone to drive the entire process, which generally requires the accumulation of additional oncogenic mutations (i.e. in EGFR, KRAS or ALK, to mention some), whose molecular signals eventually funnel through Myc for the execution of their transcriptional programs. In this context, as reported in several in vitro and in vivo studies in both mouse and human experimental models (partly summarized in this article), Myc appears to become an essential function for tumor progression and maintenance. This phenomenon is frequently referred to as ‘oncogene addiction’ and it constitutes an important vulnerability for the treatment of cancer in general. Myc addiction in our view appears to be a great opportunity for the treatment of lung cancer.
Emerging serine-threonine kinase inhibitors for treating ovarian cancer
Published in Expert Opinion on Emerging Drugs, 2019
Asaf Maoz, Marcia A. Ciccone, Shinya Matsuzaki, Robert L. Coleman, Koji Matsuo
This review summarizes the available data for a limited number of STK inhibitors that were included based on their advanced clinical development stage for the treatment of ovarian cancer. The main pathways targeted by these drugs include the PI3K-AKT-mTOR, the RAS-RAF-MEK, and the Aurora kinase pathways. The majority of the STK kinome has not been clinically targeted in ovarian cancer, and basic research continues to identify potential targetable STKs, such as those involved in DNA repair [108,109], including WEE1, CHK1, CHK2, and others. STK inhibitors reviewed here and previously [20] have yet to show a clear benefit in patient-centered outcomes of improving quality of life or overall survival, despite encouraging preclinical data. This suggests that oncogene addiction may not occur with these STKs and that intrinsic and acquired resistance to their inhibition is common. For such agents to be effective in multiple settings, primary, the recurrent and metastatic disease would need to demonstrate the same oncogenic pathway addiction.