Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer

Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi; Wang, Yi Jun; Misale, Sandra; Bardelli, Alberto; Yu, Jian; Zhang, Lin

doi:10.1038/s41388-018-0289-x

Cited by 29 publications

(30 citation statements)

References 44 publications

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“…37 Studies have shown that induction of PUMA relates closely with varying sensitivity to EGFR TKIs in neck and head cancer cells, and of the absence of PUMA induction correlates with resistance to EGFR TKIs. 8,43 Increased expression of PUMA is associated with superior prognosis in stage II and III CRC patients undergoing 5-FU-based therapy. 44 Therefore, induction of PUMA F I G U R E 4 Activation of p65 mediates PUMA induction in response to gilteritinib treatment.…”

Section: Discussionmentioning

confidence: 99%

“…8,37 To determine reporter activities, cells were transfected with the reporters with WT or mutant PUMA, in addition to pCMVβ (Promega) used as the transfection control harbouring β galactosidase reporter. 8,37 To determine reporter activities, cells were transfected with the reporters with WT or mutant PUMA, in addition to pCMVβ (Promega) used as the transfection control harbouring β galactosidase reporter.…”

Section: Reporter Assaymentioning

confidence: 99%

“…Constructs of luciferase reporter in pBV-Luc vector containing mutant or WT PUMA promoter sequence were made as described. 8,37 To determine reporter activities, cells were transfected with the reporters with WT or mutant PUMA, in addition to pCMVβ (Promega) used as the transfection control harbouring β galactosidase reporter.…”

Section: Reporter Assaymentioning

confidence: 99%

“…2,4 With the development of antitumour agents that are specifically targeted, chemotherapy against metastatic CRC has undergone significant improvement. [6][7][8] Thus, more personalized treatments are expected with the advent of specialized targeted therapy in the field of oncological procedures. [6][7][8] Thus, more personalized treatments are expected with the advent of specialized targeted therapy in the field of oncological procedures.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 For instance, Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is functional singly, or along with cytotoxic drugs for of the therapy of metastatic CRC. [6][7][8] Thus, more personalized treatments are expected with the advent of specialized targeted therapy in the field of oncological procedures.…”

Section: Introductionmentioning

confidence: 99%

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Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

Lin

et al. 2019

J Cellular Molecular Medi

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As a highly potent and highly selective oral inhibitor of FLT3/AXL, gilteritinib showed activity against FLT3D835 and FLT3-ITD mutations in pre-clinical testing, although its role on colorectal cancer (CRC) cells is not yet fully elucidated. We examined the activity of gilteritinib in suppressing growth of CRC and its enhancing effect on other drugs used in chemotherapy. In this study, we observed that, regardless of p53 status, treatment using gilteritinib induces PUMA in CRC cells via the NF-κB pathway after inhibition of AKT and activation of glycogen synthase kinase 3β (GSK-3β). PUMA was observed to be vital for apoptosis in CRC cells through treatment of gilteritinib.Moreover, enhancing induction of PUMA through different pathways could mediate chemosensitization by using gilteritinib. Furthermore, PUMA deficiency revoked the antitumour role of gilteritinib in vivo. Thus, our results indicate that PUMA mediates the antitumour activity of gilteritinib in CRC cells. These observations are critical for the therapeutic role of gilteritinib in CRC. K E Y W O R D SAKT/GSK-3β/NF-κB, apoptosis, colorectal cancer, gilteritinib, PUMA

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Section: Discussionmentioning

confidence: 99%

Section: Reporter Assaymentioning

confidence: 99%

Section: Reporter Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

Lin

et al. 2019

J Cellular Molecular Medi

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DPCPX induces Bim‐dependent apoptosis in nasopharyngeal carcinoma cells

Pan

Zhang

Guo

et al. 2022

Cell Biology International

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ADORA1 promotes tumor growth and development in multiple cancers. DPCPX (a selective adenosine A1 receptor antagonist), a specific ADORA1 antagonist, has shown antitumor effects in many cancer types. Nevertheless, the function of DPCPX in nasopharyngeal carcinoma (NPC) still remains to be unraveled. In this study, we investigated the functional role of DPCPX on NPC cells. We found that DPCPX promotes NPC cells growth inhibition. DPCPX induced Bim-dependent apoptosis in NPC cells irrespective of p53 status via the FoxO3a pathway following PI3K/AKT inhibition. Furthermore, DPCPX enhanced the antitumor effect of cisplatin, 5-FU and Paclitaxel in NPC. Xenograft experiment revealed that deficiency of Bim in vivo stalls apoptosis and antitumor activity of DPCPX. In conclusion, the PI3K/AKT/ FoxO3a/Bim axis plays a critical role in the anticancer effects of DPCPX in NPC.

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Immunogenic cell death in colon cancer prevention and therapy

Ruan

Leibowitz

Zhang

et al. 2020

Molecular Carcinogenesis

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Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The colonic mucosa constitutes a critical barrier and a major site of immune regulation. The immune system plays important roles in cancer development and treatment, and immune activation caused by chronic infection or inflammation is well-known to increase cancer risk.During tumor development, neoplastic cells continuously interact with and shape the tumor microenvironment (TME), which becomes progressively immunosuppressive. The clinical success of immune checkpoint blockade therapies is limited to a small set of CRCs with high tumor mutational load and tumor-infiltrating T cells. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, can therefore help break the immunosuppressive TME, engage the innate components, and prime T cellmediated adaptive immunity for long-term tumor control. In this review, we discuss the current understanding of ICD induced by antineoplastic agents, the influence of driver mutations, and recent developments to harness ICD in colon cancer. Mechanism-guided combinations of ICD-inducing agents with immunotherapy and actionable biomarkers will likely offer more tailored and durable benefits to patients with colon cancer. K E Y W O R D S cancer prevention, cancer therapy, colon cancer, immunogenic cell death 1 | INTRODUCTION Colorectal cancer (CRC) is a major cancer-related killer worldwide, with an increased incidence projected in many developing countries. The survival rate of metastatic CRC remains low at around 11%. 1 Most sporadic CRCs develop from benign preneoplastic polyp-like lesions following somatic inactivation of the APC tumor suppressor and progress with a series of genetic and epigenetic alterations accumulated over years or decades in KRAS/BRAF, SMAD/TGFBR2, p53, and PIKCA3 among others. 2 Existing research has highlighted critical interactions between the immune system and emerging tumor cells, and the complex changes in the tumor microenvironment (TME) during cancer progression toward immunosuppression and loss of immunosurveillance. 3 Cancer cell-intrinsic mechanisms are believed to play a key role in shaping local immune landscapes and therapeutic responses. 4 The breakthrough in immune checkpoint blockade (ICB), such as antibodies against programmed cell death-1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), 5,6 supports immune normalization or restoration in tumor control. 7 However, T-cell activating therapies have limited success in solid tumors. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, is,therefore, an attractive approach to break the immunosuppressive TME and re-establish immune surveillance by engaging both the innate and adaptive components. 8,9 ICD can be induced by a variety of chemopreventive agents, radiation, chemotherapeutics, and targeted therapies, and is shown to be critical for the antitumor effects in preclinical models through a...

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Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer

Cited by 29 publications

References 44 publications

Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

DPCPX induces Bim‐dependent apoptosis in nasopharyngeal carcinoma cells

Immunogenic cell death in colon cancer prevention and therapy

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