Tumors driven by <i>RAS</i> signaling harbor a natural vulnerability to oncolytic virus M1

Cai, Jing; Lin, Kaiying; Cai, Wei; Lin, Yuan; Liu, Xincheng; Guo, Li; Zhang, Jifu; Xu, Wencang; Lin, Ziqing; Wong, Chun-Wa; Sander, Max; Hu, Jun; Gao, Yan; Zhu, Wenbo; Liang, Jiankai

doi:10.1002/1878-0261.12820

Cited by 8 publications

(9 citation statements)

References 41 publications

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“…Many OVs depend on oncogenic signaling pathway that are constitutively activated in cancer cells for their selective viral replication and oncolysis. For example, a number OVs depend on activated Ras pathway for their replication, including reovirus [ 109 ], influenza A virus delINS1 [ 110 ], poxvirus Pexa-Vec [ 42 ], coxsackievirus Type B3 [ 111 ], and alphavirus M1 [ 112 ]. For alphavirus M1, there have been four biomarkers identified thus far that correspond to increased OV activity: zinc-finger antiviral protein (ZAP), inositol-requiring kinase 1α, Ras homolog family member Q, and mutated and activated KRAS [ 113 ].…”

Section: Oncolytic Viruses and Immunotherapy: Overviewmentioning

confidence: 99%

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

et al. 2022

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Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.

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Section: Oncolytic Viruses and Immunotherapy: Overviewmentioning

confidence: 99%

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

et al. 2022

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“…The search for predictive biomarkers for various oncolytic viruses is ongoing; to date, a few conclusive biomarkers have been identified, including reovirus requiring activated Ras signaling 23 and vesicular stomatitis virus (VSV) requiring defects in the IFN pathway. 24 Four biomarkers for M1 virus have been identified: zinc-finger antiviral protein (ZAP), 16 inositol-requiring kinase 1a (IRE1a), 25 ras homolog family member Q (RHOQ), 26 and K-RAS mutation 27 (Fig. 1).…”

Section: Mechanism Of Action: Biomarkers For Precise Treatment Of M1 mentioning

confidence: 99%

“…[34][35][36] The relationship between M1 viral infection and oncogenic mutations in a large panel of tumor cell lines has been analyzed, and among oncogenic mutations, K-RAS mutation correlated with the oncolytic efficiency of M1 virus. 27 Experimental elimination of the K-RAS mutation renders tumor cells resistant to M1 virus. The oncogenic RAS/RAF/MEK pathway promotes the replication and oncolytic effect of M1 virus by inhibiting expression of the key antiviral factor CDKN1A, also known as p21.…”

Section: K-ras Mutationmentioning

confidence: 99%

“…The oncogenic RAS/RAF/MEK pathway promotes the replication and oncolytic effect of M1 virus by inhibiting expression of the key antiviral factor CDKN1A, also known as p21. 27 Despite more than three decades of intensive effort, no effective pharmacological inhibitors of RAS oncoproteins are available in the clinic, promoting the widely held perception that RAS proteins are ''undruggable.'' 37,38 Nonetheless, M1 virus might offer renewed hope for the treatment of cancer with abnormal RAS activation and transform RAS-driven tumors to be ''druggable.''…”

Section: K-ras Mutationmentioning

confidence: 99%

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The Identification and Development of a Novel Oncolytic Virus: Alphavirus M1

Cai

Gao

2021

Human Gene Therapy

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Oncolytic virotherapy represents an ideal therapeutic platform for cancer in which natural or engineered viruses selectively replicate in and destroy tumor cells, whereas sparing normal cells. Oncolytic virotherapy is considered as a key contributor in modern immunotherapy. However, several challenges remain with regard to exploiting the potential of oncolytic viruses, such as the lack of biomarkers for precise treatment, the difficulty of systemic administration because of pre-existing neutralizing antibodies to popular oncolytic viral vectors in human serum and the lack of mature lyophilization technology for convenient transport and preservation of viral preparations. The M1 strain, which was isolated on Hainan Island of China in the 1960s, is a member of the alphavirus genus Togaviridae family. It was identified as a novel oncolytic virus in 2014. During the development of M1 virus, many challenges have been overcome: several biomarkers have been identified for precise treatment; systematic administration of M1 is suitable and feasible because of the extremely low percentage of pre-existing neutralizing antibodies in the general population, and a lyophilized powder that maintains high biological stability has been developed. This review provides an encyclopedia of studies supporting M1 as an oncolytic virus, including the biological characteristics, tumor selectivity and its mechanism, tumor killing mechanism, combination therapy, and nonclinical pharmacokinetics of M1 virus. The future development direction of oncolytic virus M1 is also discussed at the end of the review.

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“…Beyond small-molecule inhibitors, some innovative therapeutic approaches, such as oncolytic virus-mediated gene-editing [197], mRNA vaccines [198] and novel classes of inhibitors [199], have emerged. RAS-driven tumors have been shown to possess a natural vulnerability to the oncolytic M1 virus, which provides insights into the use of gene-editing oncolytic virotherapy in cancers bearing RAS mutations [200]. Oncolytic viruses are currently under examination and might be a promising alternative for RAS-driven cancer therapy in the upcoming years [201,202].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Tatlı

Doğanay

2021

Molecules

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Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.

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Tumors driven by RAS signaling harbor a natural vulnerability to oncolytic virus M1

Cited by 8 publications

References 41 publications

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

The Identification and Development of a Novel Oncolytic Virus: Alphavirus M1

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

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