Cell signaling and cancer: a mechanistic insight into drug resistance

Panda, Munmun; Biswal, Bijesh K.

doi:10.1007/s11033-019-04958-6

Cited by 67 publications

(36 citation statements)

References 141 publications

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“…The ability of cancers to adapt to and survive the effects of cancer therapies remains one of the greatest impediments in medical and clinical oncology. Treatment resistance directly translates to the ineffectiveness and eventual failures of cancer therapies [31,32,33,34,35,36]. Innate treatment resistance predates therapeutic intervention, whereas acquired treatment resistance is a refractory outcome of cancer therapy that occurs when subpopulations of cancer cells within tumors acquire mutations and adaptations that desensitize them to ongoing treatment [37,38,39,40,41].…”

Section: Autophagy Contributes To Treatment Resistance In Cancermentioning

confidence: 99%

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Gorski

2019

Cancers

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Despite advances in diagnostic tools and therapeutic options, treatment resistance remains a challenge for many cancer patients. Recent studies have found evidence that autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation and recycling, contributes to treatment resistance in different cancer types. A role for autophagy in resistance to chemotherapies and targeted therapies has been described based largely on associations with various signaling pathways, including MAPK and PI3K/AKT signaling. However, our current understanding of the molecular mechanisms underlying the role of autophagy in facilitating treatment resistance remains limited. Here we provide a comprehensive summary of the evidence linking autophagy to major signaling pathways in the context of treatment resistance and tumor progression, and then highlight recently emerged molecular mechanisms underlying autophagy and the p62/KEAP1/NRF2 and FOXO3A/PUMA axes in chemoresistance.

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Section: Autophagy Contributes To Treatment Resistance In Cancermentioning

confidence: 99%

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Gorski

2019

Cancers

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“…Based on previous studies, many factors are associated with the development of chemoresistance, including changes in the activity of membrane transporters, increased drug metabolism, alteration of drug targets, epithelial-mesenchymal transition (EMT), and tumor heterogeneity, all of which can affect the sensitivity of cancer cells to chemotherapeutic drugs (4,5). Furthermore, drug resistance-related genes (such as MDR and LRP) and various signaling pathways (such as MAPK, Wnt, and Notch) are reported to be significant causes of chemoresistance (6). However, the molecular mechanisms of chemoresistance are still not fully understood, and more research is needed to discover and develop effective biomarkers and targets for GC chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer

et al. 2020

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Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.

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“…These results suggest that TGFβ and Notch activation may contribute to resistance to anti-PD-1 therapy. While both TGFβ and Notch pathways have been associated with tumor progression 34,35 and poorer response to chemotherapy 36 and targeted therapy, 37,38 emerging evidence suggests a similar role in response to cancer immunotherapy. TGFβ is a pleotropic cytokine with well-documented immunosuppressive functions, including the expansion of T regulatory cells and suppression of proliferation and activity of effector T cells and NK cells.…”

Section: Discussionmentioning

confidence: 99%

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy

et al. 2021

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Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or β2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFβ and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFβ and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

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Cell signaling and cancer: a mechanistic insight into drug resistance

Cited by 67 publications

References 141 publications

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy

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