Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Murphy, Kendelle J.; Zhu, Jessie; Trpceski, Michael; Pereira, Brooke A.; Timpson, Paul; Herrmann, David

doi:10.1042/bst20220162

Cited by 11 publications

(10 citation statements)

References 110 publications

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“…FAK-dependent fibrotic stromal reaction and collagen IV deposition are responses to chemotherapy in pancreatic cancer. Hence, FAK inhibitor is predicted to synergize with chemotherapy by promoting cancer cell apoptosis and altering stromal reaction [111,112]. FAK inhibitor increases the proportion of cells in the S-G2-M cell cycle induced by AG in pancreatic cancer [111] and increases 5-FU-induced caspase-3 activity in a p53-dependent manner in gastric cancer [113].…”

Section: Targeted Therapy To Synergize With Chemotherapymentioning

confidence: 99%

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

Peng

Ying

Zhang

et al. 2023

Cancers

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The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.

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Section: Targeted Therapy To Synergize With Chemotherapymentioning

confidence: 99%

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

Peng

Ying

Zhang

et al. 2023

Cancers

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“…Other stroma targeting strategies, albeit without biomarker selection, include the vitamin D receptor agonist paricalcitol with chemo-and immunotherapy, 109 focal adhesion kinase inhibition with defactinib, VS-6766 or IN10018 with chemotherapy, radiotherapy and/or ICI (NCT02758587, NCT02546531, NCT04331041), 110 and connective tissue growth factor (CTGF/CCN2) blockade with pamrevlumab (FG-3019) with chemotherapy and/or ICI (NCT04449004, NCT03941093, NCT03727880, NCT04331041) (Table 2). 111 Fibroblast activating protein (FAP) is a type II membrane bound glycoprotein which activates cancer-associated fibroblasts.…”

Section: Tumor Mutational Burdenmentioning

confidence: 99%

The role of molecular testing in pancreatic cancer

Zhen,

Safyan,

Konick

et al. 2023

Therap Adv Gastroenterol

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Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRASG12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5–10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody–drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor – T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine.

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“…Therefore, inhibiting FAK activity can dramatically suppress CAF migration and extracellular matrix deposition[ 120 ]. Meanwhile, FAK inhibition can also resensitize PDAC cells to chemotherapy[ 121 ]. Some tyrosine kinase inhibitors such as cabozantinib, pazopanib, lenvatinib, and surufatinib are under clinical evaluation for the treatment of pancreatic neuroendocrine tumors[ 122 ].…”

Section: Treatment Optionsmentioning

confidence: 99%

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options

Zhang¹,

Liu²,

Yang³

2022

World J Gastroenterol

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Pancreatic cancer (PC) is the third-leading cause of cancer deaths. The overall 5-year survival rate of PC is 9%, and this rate for metastatic PC is below 3%. However, the PC-induced death cases will increase about 2-fold by 2060. Many factors such as genetic and environmental factors and metabolic diseases can drive PC development and progression. The most common type of PC in the clinic is pancreatic ductal adenocarcinoma, comprising approximately 90% of PC cases. Multiple pathogenic processes including but not limited to inflammation, fibrosis, angiogenesis, epithelial-mesenchymal transition, and proliferation of cancer stem cells are involved in the initiation and progression of PC. Early diagnosis is essential for curable therapy, for which a combined panel of serum markers is very helpful. Although some mono or combined therapies have been approved by the United States Food and Drug Administration for PC treatment, current therapies have not shown promising outcomes. Fortunately, the development of novel immunotherapies, such as oncolytic viruses-mediated treatments and chimeric antigen receptor-T cells, combined with therapies such as neoadjuvant therapy plus surgery, and advanced delivery systems of immunotherapy will improve therapeutic outcomes and combat drug resistance in PC patients. Herein, the pathogenesis, molecular signaling pathways, diagnostic markers, prognosis, and potential treatments in completed, ongoing, and recruiting clinical trials for PC were reviewed.

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Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Cited by 11 publications

References 110 publications

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

The role of molecular testing in pancreatic cancer

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options

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