Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Carvalho, Patrícia Dias; Machado, Ana Luísa; Martins, Francisco Vitorino; Seruca, Raquel; Velho, Sérgia

doi:10.3390/cancers11122010

Cited by 38 publications

(54 citation statements)

References 94 publications

(98 reference statements)

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“…Moreover, reduced ACAA1 expression is associated with lower overall survival in various types of cancer, indicating that ACAA1 acts as a tumor suppressor in a wide range of malignancies. Oncogenic KRAS enhances immune checkpoint inhibitor efficacy by providing an inflammatory tumor microenvironment (24). Additionally, oncogenic KRAS also increases tumor PD-L1 expression and promotes CD8 + cells infiltration into the tumor stroma (22).…”

Section: Discussionmentioning

confidence: 99%

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ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

Feng

Shen

2020

Front. Oncol.

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Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancers. KRAS mutation is the second most prevalent mutation in NSCLC. KRAS mutant cancer cells suppress the anti-tumor T cell response. However, the underlying mechanism is still unknown. Here, we analyzed the differential expression of acetyl-CoA acyltransferase 1 (ACAA1) in various types of cancers using the TIMER database and validated the results in the NSCLC cell line H1944. We silenced oncogenic KRAS by siRNA targeting KRAS G13D , and employed an MAPK signaling pathway inhibitor to clarify the possible regulatory pathway. Moreover, we analyzed the correlation of ACAA1 expression level with B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. Correlations between expression of ACAA1 and several biomarkers of mutation burden were also tested. Finally, we evaluated the prognostic value of ACAA1 in a wide range of cancers using the Kaplan-Meier Plotter Database. We found lower expression of ACAA1 in tumor tissue than in adjacent normal tissue in various cancers. This result was confirmed using a GEO dataset. Knock-down of mutant KRAS resulted in increased ACAA1 mRNA level in H1944 cells. ACAA1 mRNA level was significantly upregulated in H1944 after treatment with MAPK pathway inhibitor sorafenib, indicating that oncogenic KRAS may downregulate ACAA1 through MAPK signaling. ACAA1 was negatively correlated with biomarkers of tumor mutation burden, including BRCA1, ATM, ATR, CDK1, PMS2, MSH2, and MDH6. Conversely, ACAA1 expression was positively correlated with infiltrating CD4 + cells and with Th1, Th2, Treg cells in the lung tumor microenvironment. Finally, we showed that ACAA1 is a predictive factor for survival in several cancer types. In summary, decreased ACAA1 expression is correlated with poor prognosis and decreases immune infiltration of CD4 + T cells in LUAD and LUSC. ACAA1 also predicts T cell exhaustion in LUSC. The mechanism underlying KRAS/ACAA1 axis-mediated regulation of immune cell infiltration requires further investigation.

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Section: Discussionmentioning

confidence: 99%

“…On the day of treatment, 5 µM or 10 µM of pathway inhibitor were added to the wells. The cells were collected at different timepoints (6,12,24, and 48 h) after treatment, and total RNA and protein were extracted using Trizol or NP40 cell lysis buffer. Subsequently, the RNA was used for q-PCR analysis.…”

Section: Mapk Pathway Inhibitionmentioning

confidence: 99%

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

Feng

Shen

2020

Front. Oncol.

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“…KRAS, the most commonly mutated driver oncogene in LUAD, remains notoriously untargeted. What is more, its mutations are mutually exclusive with EGFR mutations, so patients with KRAS mutations are resistant to EGFR targeted treatment and are faced with no efficient treatment options and a poor prognosis [10,11]. Encouragingly, the KRAS G12C inhibitor sotorasib can potentially be the first approved targeted therapy for patients with KRAS G12C -mutant NSCLC [12].…”

Section: Introductionmentioning

confidence: 99%

“…Despite these encouraging results, increased immune tolerance is often documented in many cancers [21], implying that there is more to learn about the cross-talk between the developing tumors and the immune cells within the TME. Interestingly, KRAS mutations are increasingly shown to affect tumor interactions with the surrounding TME [11,[22][23][24][25]. Below we will discuss the main mechanisms of tumor immune resistance, with a special emphasis on LUAD and mutant KRAS-mediated effects underlying immune resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Immune Resistance in Lung Adenocarcinoma

Spella

Stathopoulos

2021

Cancers

109

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Lung cancer is the leading cancer killer worldwide, imposing grievous challenges for patients and clinicians. The incidence of lung adenocarcinoma (LUAD), the main histologic subtype of lung cancer, is still increasing in current-, ex-, and even non-smokers, whereas its five-year survival rate is approximately 15% as the vast majority of patients usually present with advanced disease at the time of diagnosis. The generation of novel drugs targeting key disease driver mutations has created optimism for the treatment of LUAD, but, as these mutations are not universal, this therapeutic line benefits only a subset of patients. More recently, the advent of targeted immunotherapies and their documented clinical efficacy in many different cancers, including LUAD, have started to change cancer management. Immunotherapies have been developed in order to overcome the cancer’s ability to develop mechanisms of immune resistance, i.e., to adapt to and evade the host inflammatory and immune responses. Identifying a cancer’s immune resistance mechanisms will likely advance the development of personalized immunotherapies. This review examines the key pathways of immune resistance at play in LUAD and explores therapeutic strategies which can unleash potent antitumor immune responses and significantly improve therapeutic efficacy, quality of life, and survival in LUAD.

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“…As KRAS has been determined to be mutated in around 45% of CRC patients, much research has been pursued to develop an inhibitor for mutant KRAS [ 13 ]. However, despite many years of research, there are still no therapies available that target mutant KRAS in CRC [ 14 , 15 ]. Other treatments that indirectly target mutant KRAS are thus urgently sought after in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer

Shifteh

Sapir

Pahmer

et al. 2020

Cancers

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Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.

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Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Cited by 38 publications

References 94 publications

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

Immune Resistance in Lung Adenocarcinoma

Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer

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