Cancer vaccines: Targeting KRAS-driven cancers

Zhang, Ying; Ma, Jin’an; Zhang, Haixia; Jiang, Yueping; Luo, Wenhao

doi:10.1080/14760584.2020.1733420

Cited by 41 publications

(31 citation statements)

References 82 publications

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“…TP53 inactivation occurs in $70% of PDA cases, and recurrent non-synonymous mutations within the DNA-binding domain constitute 25%-30% of these cases (Baugh et al, 2018). Mutant KRAS and p53 have long been explored as cancer vaccine targets (Vermeij et al, 2011;Zhang et al, 2020). Although T cell responses to mKRAS and p53 may be induced in select patients, most studies are underpowered to demonstrate clinical benefit and fail to clearly define human leukocyte antigen (HLA)-restricted immunogenic epitopes.…”

Section: Mkras As a Tumor Antigenmentioning

confidence: 99%

Challenges and Opportunities for Pancreatic Cancer Immunotherapy

2020

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Section: Mkras As a Tumor Antigenmentioning

confidence: 99%

Challenges and Opportunities for Pancreatic Cancer Immunotherapy

2020

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“…The mutations in the GTP-binding site confer resistance to GTP hydrolysis by GAPs, resulting in constitutively active KRAS ( 5 ). Hyperactive KRAS induces oncogenic transformation by upregulating downstream signaling pathways, including PI3K/AKT/mTOR, RAF/MEK/ERK, MAPK/ERK, and RALGEF/RAL ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting the undruggable oncogenic KRAS: the dawn of hope

Asimgil¹,

Ertetik²,

Cevik³

et al. 2022

JCI Insight

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KRAS mutations are the drivers of various cancers, including non–small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.

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“…Other strategies to boost the immune response against KRAS-mutant cancers include STING agonists (ADU-S100, MK-1454) [101,144,145], as well as CAR-T cells (adoptive T-cell transfer) [146] and mRNA vaccine technology [147]. For the latter, the current worldwide first use of mRNA vaccine technology to fight the COVID-19 pandemic [148,149] could boost its development and acceptance in the field of oncology.…”

Section: Conclusion and Future Perspectives Of Combination Therapeutmentioning

confidence: 99%

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

Köhler

2021

IJMS

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Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.

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Cancer vaccines: Targeting KRAS-driven cancers

Cited by 41 publications

References 82 publications

Challenges and Opportunities for Pancreatic Cancer Immunotherapy

Challenges and Opportunities for Pancreatic Cancer Immunotherapy

Targeting the undruggable oncogenic KRAS: the dawn of hope

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

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