Patric Jan Jansson

Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.

High-risk neuroblastoma remains a clinically challenging childhood tumor with a 5-year survival of only 50%. Tumors overexpressing N-MYC or c-MYC oncoproteins define a group of MYC-driven high-risk neuroblastoma with the most dismal outcomes, mainly caused by treatment failure due to the emergence and regrowth of multidrug-resistant cancer cells. Specific mitochondrial processes have been implicated in the maintenance of aggressive stem-like phenotypes in various cancers. We have recently identified a novel mitochondria-mediated mechanism of neuroblastoma multidrug resistance. However, the potential of pharmacological targeting of mitochondria to overcome therapy resistance and stemness in neuroblastoma remains unclear. Here, we show that c-MYC/N-MYC-driven multidrug-resistant neuroblastoma cells are highly vulnerable to cell death induced by the inhibition of mitochondrial translation. In contrast with normal fibroblasts, doxycycline (DOXY)-mediated inhibition of mitochondrial ribosomes efficiently impaired the survival of neuroblastoma cells regardless of their multidrug resistance and stem-like phenotypes. Mechanistically, inhibiting mitochondrial translation induced the mitochondrial stress-activated integrated stress response (ISR) via the OMA1-eIF2α axis, which preceded neuroblastoma cell death. Strikingly, several oncoproteins associated with poor neuroblastoma prognosis, including c-MYC and N-MYC, were markedly downregulated upon ISR activation. Comparing models of various neuroectodermal tumors and normal fibroblasts, we identified high levels of phosphorylated c-MYC and N-MYC (indicating their activity and rapid turnover) as a factor that predetermines susceptibility of neuroblastoma cells to DOXY-induced cell death. Neuroblastoma cells failed to develop significant DOXY resistance over a long-term repeated (pulsed) selection pressure, further demonstrating mitochondrial protein balance as a clinically relevant vulnerability of cancer cells that rely on high MYC activity. Together, our findings provide insight into mitochondrial retrograde regulatory networks in the context of MYC dependence and demonstrate the mitochondrial translation machinery as a promising therapeutic target in multidrug-resistant MYC-driven neuroblastoma.

Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.

Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.

Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.

Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.