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Genetic variations affecting response of radiotherapy
Journal of Genetic Medicine 2022;19:1-6
Published online June 30, 2022;  https://doi.org/10.5734/JGM.2022.19.1.1
© 2022 Korean Society of Medical Genetics and Genomics.

Eun Kyung Choi1,2,*

1Department of Radiation Oncology, 2Asan Preclinical Evaluation Center for Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Eun Kyung Choi, M.D., Ph.D. https://orcid.org/0000-0002-5265-7640
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea.
Tel: +82-2-3010-4432, Fax: +82-2-3010-6950, E-mail: ekchoi@amc.seoul.kr
Received January 10, 2022; Accepted April 30, 2022.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Radiation therapy (RT) is a very important treatment for cancer that irradiates a large amount of radiation to lead cancer cells and tissues to death. The progression of RT in the aspect of personalized medicine has greatly advanced over the past few decades in the field of technical precision responding anatomical characteristics of each patient. However, the consideration of biological heterogeneity that makes different effect in individual patients has not actually applied to clinical practice. There have been numerous discovery and validation of biomarkers that can be applied to improve the efficiency of radiotherapy, among which those related to genomic information are very promising developments. These genome-based biomarkers can be applied to identify patients who can benefit most from altering their therapeutic dose and to select the best chemotherapy improving sensitivity to radiotherapy. The genomics-based biomarkers in radiation oncology focus on mutational changes, particularly oncogenes and DNA damage response pathways. Although few have translated into clinically viable tools, there are many promising candidates in this field. In this review the prominent mutation-based biomarkers and their potential for clinical translation will be discussed.
Keywords : Radiation therapy, Genomics, Biomarkers, Mutation, Clinical trial.
Introduction

Despite advances in translational research, cancer remains the biggest challenge for human health. In recent years, several strategies have been developed from the perspective of precision medicine in modalities of cancer treatment such as surgery, chemotherapy, radiation therapy (RT), targeted therapy, immunotherapy and combinations of those [1]. Among them, RT killing cancer cells using high-energy photon radiation such as X-ray and gamma-ray has long been an important modality for cancer treatment, so the development of precision medicine in this field is expected to have a great effect. Indeed, more than half of patients receive RT in clinical cancer treatment, which is frequently combined with other cancer modalities, but in some cases RT is the only option for the treatment [2].

Mechanically innovative technologies have developed rapidly and have actually contributed greatly to improving RT efficiency. For example, image-guided radiation therapy (IGRT) is a method of improving the accuracy of radiation delivery using images. The linear accelerator is equipped with imaging technology that can adjust radiation beam to more accurately target to the tumor of patients. For IGRT, ultrasound, magnetic resonance imaging, X-ray images, computer tomography scans, 3-dimensional body surface mapping, and colored ink tattoos on the skin can be used [3]. Intensity-modulated radiation therapy (IMRT) is an advanced mode of high-precision RT that uses a computer-controlled linear accelerator to deliver accurate radiation doses to a malignant tumor or specific area within the tumor. In order to further increase IMRT efficiency, combination with artificial intelligence has recently been attempted [4]. In addition, volumetric arc therapy (VMAT), stereotactic body radiation therapy (SBRT), particle therapy, and repository-correlation 4-dimensional cell beam computer tomography (CBCT) have contributed to the improvement of technical precision of RT [5].

Although the above-mentioned innovative technology significantly improved the effectiveness of RT, it is still difficult to treat tumors with RT alone due to lack of interpretation and application of cancer biological characteristics such as tumor heterogeneity and genetic differences between patients. It is known that the biological effects of RT to kill cancer cells and tumor tissue occur through the direct or indirect mechanisms (Fig. 1) [6]. In the direct action, the energy of radiation directly damages of genomic DNA in nuclei and induces a single strand DNA break (SSDB) or double strand DNA break (DSDB) leading cell cycle arrest and cell death such apoptosis or necrosis. In the case of indirect action, radiation induces the production of reactive oxygen species by the radiolysis of a large amount of water and oxygen that causes cellular stress ultimately changing the cell signaling pathway. There are many types of DNA damages such as base change, SSDB, DSDB, cross-linkage with protein or with other DNA molecules can be involved in biological effect of RT.

While advances in mechanical accuracy have been well applied in current radiation oncology practices, the biological heterogeneity between tumors appearing among patients has been rarely utilized. The biological heterogeneity of tumors among patients is attributable to 1) differences in genomic DNA such as mutations or chromosomal abnormalities; 2) differences in transcriptomes such as individual or multiple gene expressions; 3) epigenetic differences such as DNA methylation and histone variants; 4) non-genetic differences such as human papillomavirus (HPV). These biological differences could be utilized to develop biomarkers or measurable properties to predict the outcome of diseases for RT. Most of the treatments referencing genomic information in radiation oncology focus on mutation-based changes, especially those involved in tumor genes and DNA damage response (DDR) pathways. Although there are many promising candidates that are noteworthy for clinical application as valuable results from molecular biological studies, few have been translated into clinical practice as an effective tool [7]. This review will discuss some of famous mutation-based biomarker genes, roles in radiation responses, and clinical applicability.

DNA Damage Responding Genes

One of the direct biological reactions by radiation is DNA damage, such as DSDB or SSDB. Mutations of the genes responding DNA-damage that induce cellular signaling to determine cell fate are very important for the response of RT. These DDR genes include Ataxia Telangiectasia-Mutated (ATM) gene and Ataxia Telangiectasia and Rad3-related (ATR) gene involved in early responding DNA damages, CHK1 and CHK2 followed them, and p53 regulating the cell cycle transition by intermediately linking upstream signals. In addition, BRCA1/2 and others involved in homologous recombination DNA repair are critical biomarker genes for RT response and prognosis prediction.

ATM and ATR are the genes that respond earliest to the DNA damaged by ionizing radiation and play an important role in the DDR signal pathway, in which each other’s signal pathways harmonize properly [8]. ATM is recruited to the site of DSDB with the MRE11-RAD50-NBS1 (MRN) complex and promote to repair the damaged DNA [9]. In many types of cancer such as lung, prostate, and pancreatic cancers, the mutation of ATM is often found [10]. The recruited ATM on the damaged DNA is activated by phosphorylation and mediated the phosphorylation of p53 and CHK2, subsequently leads to arrest of cell cycle at the G1 checkpoint [9]. ATR is recruited on the site of stalled replication fork or SSDB [11] and induce the phosphorylation of CHK1, by which cell cycle arrest at the intra-S-phase or G2/M phase is mediated. There are clinical investigations with ATM or ATR inhibitors to improve radiotherapeutic efficacy. The VX-970 known as berzosertib inhibiting mainly ATR and mildly ATM is being on a phase II clinical trial (NCT03641313) to enhance radiosensitivity for p53-mutated gastric or esophageal cancers. AZD6738 known as ceralasertib, the ATR inhibitor has displayed improved anti-tumor effects in ATM-deficient models including cell lines and xenograft tumor of non-small cell lung carcinoma (NSCLC) [12] as well as other ATM deficient cell lines like gastric and pancreatic cancers [13-15].

DNA Repairing Genes

There are genes and signal pathways that actively attempt to repair the damaged DNA responding radiation-induced DNA damage. poly (ADP-ribose) polymerase (PARP), one of the DNA repairing gene recognizes and binds onto SSDS and implements repair of DNA in the manner of BRCA1/2-dependent homologous recombination (HR). Application of PARP inhibitors, such as olaparib for the treatment of BRCA1/2-deficient tumors is well-known example of precision medicine [16,17]. The olaparib clearly showed significant effect of radiosensitization in BRCA1-deficient high-grade serious ovarian carcinoma (HGSOC) cells, but not in BRCA1-competent HGSOC cells [18]. Many of phase I clinical trials investigating PARP inhibitors for radiosensitization, although just few investigate whether competency in the homologous recombination DNA repair pathway related to BRCA1/2 genetic integrity influences the radiosensitization. In a phase I/II clinical trial (NCT03317392), the efficacy of olaparib combined with radium Ra-223 is being assessed in patients of metastatic prostate cancer, in which comparing progression-free survival (PFS) between patients with homologous recombination deficient or proficient tumor is included. Another study assesses the radiosensitization effect of copanlisib, olaparib, and durvalumab in advanced solid tumors with germline or somatic DDR pathway gene mutations such as BRCA1/2, ATM, ATRX, or other DDR-related genes.

Growth Signaling Genes

The genes regulating cancer cell growth including epidermal growth factor receptor (EGFR), KRAS, BRAF and others are known to be involved in the outcome response of radiotherapy.

For the precision treatment of cancers including NSCLC and head and neck squamous cell carcinoma (HNSCC), the most well studied biomarker is EGFR. EGFR, called equally ErbB-1 or HER1 is a transmembrane receptor of the epidermal growth factor family (EGF family) of extracellular protein ligands [19]. The expression of EGFR is closely related to acceleration of cell proliferation, enhancing survival against death signal and pathway of DDR. Overexpression of EGFR is associated with resistance of radiotherapy through enhancing cancer cell proliferation in HNSCC and NSCLC during fractions of treatment [20]. Previous studies have provided two important meanings of EGFR as a biomarker for RT response. One is that hypofractionated RT is beneficial for the patients with EGFR overexpression because of shortened overall treatment time and more effective killing of cancer cells [21]. The other is that EGFR inhibitors should be potent for radiosensitization during RT [22]. Indeed, clinical trials using EGFR inhibitors are ongoing in RT for locally advanced NSCLC with gain-of-function mutations of EGFR. NCT01553942 is a phase II trial that uses afatinib as induction therapy before concurrent chemoradiotherapy in stage IIIA NSCLC with EGFR-mutations. Cetuximab that is an EGFR-targeted therapeutic antibody showed promising results as a radiosensitizer in pre-clinical studies, but demonstrated much less effectiveness than cisplatin in many phase III clinical trials in HNSCC [23,24]. Nonetheless, cetuximab still remains as an option for the patients not responding to cisplatin. In addition, there was a notable finding from phase III randomized trial called EXTREME that the combination of cetuximab with concurrent chemoradiotherapy using platinum-doublet such as cisplatin and F-5U or carboplatin and 5-FU with lead to improved therapeutic efficacy and median overall survival (OS) compared to the standard platinum-doublet alone [25].

The KRAS is an oncogene that is found frequently mutated and constitutively active in many types of cancers [26-28]. The protein relays signals from outside of the cells to promote pathway of growth signal through MEK and ERK, activating the MAPK, PI3K, and RAL-GEL pathways [29]. KRAS acts as a molecular on/off switch for cell proliferation signaling using protein dynamics in which GTP is bound in its active state and converted to GDP by an enzymatic cleave of terminal phosphate of the nucleotide. The mutations of the KRAS are associated with resistance to radiotherapy in NSCLC [30,31], rectal cancer [32,33], and liver metastasis [34], in addition to prognostic aggressiveness for disease and outcomes of poor survival. Although its significant effects in cancer biology have been sufficiently proved, KRAS has not yet been translated to druggable target [29]. Very recently the first KRAS-targeting Sotorasib is being in clinical trial. The Sotorasib inhibits the KRAS mutation of G12C and displayed promising results with 129 solid tumor patients in a Phase I clinical trial [35]. In addition to directly targeting KRAS mutations, KRAS as a biomarker provides additional opportunities for therapeutic intervention. In a phase I clinical trial (NCT01912625), MEK inhibitor Trametinib has shown potent effect of radiasensitization in the setting of KRAS mutations in combination with chemoradiotherapy in stage III NSCLC [36,37]. Additionally, multi-kinase inhibitor midostaurin displayed a effectiveness as a radiosensitizer by combination with existing chemoradiotherapy in locally advanced rectal cancer [38].

In addition to KRAS, BRAF is another important gene for consideration of genomic information-based precision radiotherapy. BRAF is a proto-oncogene encoding a serine/threonine protein kinase referred v-Raf murine sarcoma viral oncogene homolog B. Activation of B-Raf protein is an important part of the MAPK pathway and plays a role in promoting cell growth through activation of MEK1/2 [39]. This protein plays a role in regulating cellular proliferation and increased cell survival [40]. The most frequent mutation of BRAF is V600E point mutation that has been extensively researched as a driver mutation in melanoma and other cancers such colorectal, brain, NSCLC [41-44]. Point mutations in BRAF have been reported to be associated with resistance of radiotherapy [39,45,46]. The combination of BRAF inhibitors such as vemurafenib, dabrafenib with radiotherapy is being examined in many types of BRAF-mutated cancers, especially in brain metastastatic melanoma. The cell lines of melanoma with BRAF mutation showed increased radio-sensitivity in the presence of BRAF inhibitor vemurafenib, while cell lines without BRAF mutation did not [47]. The preclinical results from in vitro and in vivo experiments of BRAF-mutated high grade glioma demonstrated promising efficacy of vemurafinib combining with radiotherapy [48]. Clinical studies assessing the combined use of BRAF inhibitors and RT in melanoma brain metastases have showed promising potential [39], but the increased toxicity observed in the study particularly necrosis of skin has been remained as a substantial problems that should be overcome [48-50]. The 155 patients with BRAF-mutated metastatic melanoma were examined for the effects of interrupting treatment of BRAF inhibition during radiotherapy [51]. An ongoing clinical trial of phase II (NCT03898908) is investigating the combination of BRAF and MEK inhibitors with radiotherapy in brain-metastatic BRAF-mutated melanoma.

Conclusion

Radiation oncology is an important modality accounting for a large proportion of cancer treatments. Its mechanical technique has been innovatively developed to treat each patient's tumor uniquely according to the anatomical differences, which is a leading pioneer in precision medicine for radiation oncology. Whereas, valuable findings from the studies of molecular biology or radiation biology have not yet effectually translated into clinical practice to exploit biological differences between tumors of patients. There is still considerable potential for innovation in relation to the integration of genetic information-based treatment planning for precision radiation oncology. In this review, the genetic mutations well-known to affect response of radiotherapy have been introduced and discussed. Most validation of mutation information affecting radiotherapeutic response remains in preclinical or early clinical stages. There might be more genetic information and related biomarkers that have not yet been discovered. Therefore, more efforts are still necessary to develop precision radiation oncology utilizing genetic differences between patient tumors.

Conflict of interest

I declare that I do not have any conflicts of interests.

Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI20C1586), and by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2019R1A2C2009183).

Figures
Fig. 1. Biological mechanism of ionizing radiation (IR) in radiation therapy. IR induces direct action or indirect action to kill cancer cells. For direct action, IR induces a single strand break (SSB) or double strand break (DSB) of DNA in nuclei. For indirect action, IR induces the production of reactive oxygen species causing cellular stress ultimately changing the cell signaling pathway. Adapted from the article of Gong L et al. (Int J Nanomedicine 2021;16:1083-102) [6].
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