Is Autophagy Targeting a Valid Adjuvant Strategy in Conjunction with Tyrosine Kinase Inhibitors?

Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy.

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors.

The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease.

Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-β / Smad4 signaling pathway.

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca reducing agent, in combination with simvastatin.

A Conversation with ChatGPT on Contentious Issues in Senescence and Cancer Research.

Artificial intelligence (AI) platforms, such as Generative Pretrained Transformer (ChatGPT), have achieved a high degree of popularity within the scientific community due to their utility in providing evidence-based reviews of the literature. However, the accuracy and reliability of the information output and the ability to provide critical analysis of the literature, especially with respect to highly controversial issues, has generally not been evaluated. In this work, we arranged a question/answer session with ChatGPT regarding several unresolved questions in the field of cancer research relating to therapy-induced senescence (TIS), including the topics of senescence reversibility, its connection to tumor dormancy, and the pharmacology of the newly emerging drug class of senolytics.

Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.

The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2, and more recently also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy.

OMA1 and YME1L as a Diagnostic Panel in Hepatocellular Carcinoma.

Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation.

Making the Case for Autophagy Inhibition as a Therapeutic Strategy in Combination with Androgen-Targeted Therapies in Prostate Cancer.

Androgen receptor targeting remains the primary therapeutic strategy in prostate cancer, encompassing androgen biosynthesis inhibitors and androgen receptor antagonists. While both androgen-receptor-positive and "castration-resistant" prostate cancer are responsive to these approaches, the development of resistance is an almost inevitable outcome leading to the castration-resistant form of the disease. Given that "cytoprotective" autophagy is considered to be a predominant mechanism of resistance to various chemotherapeutic agents as well as to radiation in the cancer literature, the purpose of this review is to evaluate whether autophagy plays a central role in limiting the utility of androgen deprivation therapies in prostate cancer.

The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies.

BRAF-targeted therapies are widely used for the treatment of melanoma patients with BRAF V600 mutations. Vemurafenib, dabrafenib as well as encorafenib have demonstrated substantial therapeutic activity; however, as is the case with other chemotherapeutic agents, the frequent development of resistance limits their efficacy. Autophagy is one tumor survival mechanism that could contribute to BRAF inhibitor resistance, and multiple studies support an association between vemurafenib-induced and dabrafenib-induced autophagy and tumor cell survival.

Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors.

The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 and BRDT, at various transcription-related sites, including super-enhancers. BET inhibitors are currently under investigation both in pre-clinical cell culture and tumor-bearing animal models, as well as in clinical trials. However, as is the case with other chemotherapeutic modalities, the development of resistance is likely to constrain the therapeutic benefits of this strategy.

BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.

Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib.

Is autophagy induction by PARP inhibitors a target for therapeutic benefit?

PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies, particularly when the tumors are deficient in DNA repair pathways. However, as the case with other chemotherapeutic agents, their effectiveness is often compromised by the development of resistance. PARP inhibitors have consistently been reported to promote autophagy, a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.

Topoisomerase I poisons-induced autophagy: Cytoprotective, Cytotoxic or Non-protective.

Topoisomerase I inhibitors represent a widely used class of antineoplastic agents that promote both single-stranded and double-stranded breaks in the DNA of tumor cells, leading to tumor cell death. Topotecan and irinotecan are the clinically relevant derivatives of the parent drug, camptothecin. As is the case with many if not most anticancer agents, irinotecan and topotecan promote autophagy.

Is Autophagy Inhibition in Combination with Temozolomide a Therapeutically Viable Strategy?

Temozolomide is an oral alkylating agent that is used as the first line treatment for glioblastoma multiform, and in recurrent anaplastic astrocytoma, as well as having demonstrable activity in patients with metastatic melanoma. However, as the case with other chemotherapeutic agents, the development of resistance often limits the therapeutic benefit of temozolomide, particularly in the case of glioblastoma. A number of resistance mechanisms have been proposed including the development of cytoprotective autophagy.

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer.

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies.

Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells.

Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence.

Therapeutic Potential for Targeting Autophagy in ER+ Breast Cancer.

While endocrine therapy remains the mainstay of treatment for ER-positive, HER2-negative breast cancer, tumor progression and disease recurrence limit the utility of current standards of care. While existing therapies may allow for a prolonged progression-free survival, however, the growth-arrested (essentially dormant) state of residual tumor cells is not permanent and is frequently a precursor to disease relapse. Tumor cells that escape dormancy and regain proliferative capacity also tend to acquire resistance to further therapies.

The Cytoprotective, Cytotoxic and Nonprotective Functional Forms of Autophagy Induced by Microtubule Poisons in Tumor Cells-Implications for Autophagy Modulation as a Therapeutic Strategy.

Microtubule poisons, as is the case with other antitumor drugs, routinely promote autophagy in tumor cells. However, the nature and function of the autophagy, in terms of whether it is cytoprotective, cytotoxic or nonprotective, cannot be predicted; this likely depends on both the type of drug studied as well as the tumor cell under investigation. In this article, we explore the literature relating to the spectrum of microtubule poisons and the nature of the autophagy induced.

An overview of resistance to Human epidermal growth factor receptor 2 (Her2) targeted therapies in breast cancer.

Breast cancer (BC) is the second most common cause of cancer-related deaths and the most frequently diagnosed cancer in females. Among breast cancer types, HER2-positive breast cancer occurs in nearly 20% of human breast cancers and is associated with increased aggressiveness, poor prognosis, and shortened overall survival. HER2+ breast cancer is currently managed with multidisciplinary treatment strategies including surgery, radiation, chemotherapy, and targeted therapy.