Experimental, Clinical, and Morphological Analysis of H-Ras Oncoproteins for Locally Advanced Breast Cancer

Ainura Maratovna Zhumakayeva; K. D. Rakhimov; I. M. Omarova; S. M. Adekenov; S. S. Zhumakayeva

doi:10.3889/oamjms.2020.4969

Authors

Ainura Maratovna Zhumakayeva Department of Oncology, Karaganda Medical University, Karaganda City, Kazakhstan, “International Research and Production Holding Phytochemistry,” Karaganda City, Republic of Kazakhstan
K. D. Rakhimov Department of Clinical Pharmacology, Kazakh National Medical University Named After S.D. Asfendiyarov, Researcher at “International Research and Production Holding Phytochemistry,” Karaganda City, Republic of Kazakhstan
I. M. Omarova Department of Oncology and Radiology, Karaganda Medical University, Karaganda City, Republic of Kazakhstan
S. M. Adekenov Doctor of Chemical Sciences, General Director of “International Research and Production Holding Phytochemistry,” Karaganda City, Republic of Kazakhstan
S. S. Zhumakayeva Doctor of Chemical Sciences, General Director of “International Research and Production Holding Phytochemistry,” Karaganda City, Republic of Kazakhstan

DOI:

https://doi.org/10.3889/oamjms.2020.4969

Keywords:

Arglabin, Breast cancer, H-RAS, Farnesyl protein transferase

Abstract

BACKGROUND: Activated forms of RAS increase both in breast cancer and in cell lines in the presence of estimated glomerular filtration rate (EGFR) or HER2 expression. HRAS oncoproteins play an important role in enhancing the proliferation and resistance of breast cancer tumor cells to apoptosis. A number of studies have shown a significant decrease in EGFR expression after neoadjuvant chemotherapy, which has been clinical, manifested by an improvement in immediate efficacy and an increase in overall and relapse-free breast cancer survival rates.

AIM: The aim of the study was to study relapse-free survival depending on the expression of the H-RAS oncoprotein in patients with breast cancer who received different treatment regimens for the farnesyltransferase inhibitor.

METHODS: H-RAS status was assessed by immunohistochemistry.

RESULTS: A comparative analysis of patients with negative expression of H-RAS oncoproteins showed a statistically significant increase in relapse-free survival in the subgroups who received neoadjuvant chemotherapy according to the AC regimen (adriablastin + cyclophosphamide) and AC + arglabin, compared with monotherapy by arglabin: Kruskal–Wallis= 12.56, where p = 0.001. A comparative analysis of patients with positive expression of H-RAS showed that in the subgroups treated with arglabin and AC+arglabin, there was a statistically significant increase in relapse-free survival compared with the AC subgroup: Kruskal–Wallis = 10.96, where p = 0.004. It was established that the positive expression of H-RAS negatively affects not only the direct effectiveness of neoadjuvant therapy but also worsens the rates of relapse-free survival. However, in patients with positive H-RAS expression who received arglabin in monotherapy, there was a statistically significant increase in relapse-free survival up to 16.5 ± 1.1 months compared with the standard AC regimen (13.5 ± 1.1 months) (р ˂ 0.05), the addition of arglabin to the standard AC regime also increased this indicator to 16.4 ± 1.2 months (р ˂ 0.05).

CONCLUSION: These results may indicate the clinical applicability of determining H-RAS as a prognostic factor for relapse-free survival in breast cancer.

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References

Wright KL, Adams JR, Liu JC, Loch AJ, Wong RG, Jo CE, et al. Ras signaling is a key determinant for metastatic dissemination and poor survival of luminal breast cancer patients. Cancer Res. 2015;75(22):4960-72. https://doi.org/10.1158/0008-5472.can-14-2992 PMid:26400062

Haddad TC, Goetz MP. Landscape of neoadjuvant therapy for breast cancer. Ann Surg Oncol. 2015;22(5):1408-15. https://doi.org/10.1245/s10434-015-4405-7 PMid:25727557

King TA, Morrow M. Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol. 2015;12(6):335-43. https://doi.org/10.1038/nrclinonc.2015.63 PMid:25850554

Nurgaziev KS, Toleutaiuly K, Baipeisov DM, Ospanov SE. Development of cancer care in the republic of Kazakhstan. Young Sci. 2017;19:4-5.

OECD. Health of the Population of the Republic of Kazakhstan and the Activities of Healthcare Organizations in 2018, Stats Zhynak Astana. Paris, France: OECD; 2018. p. 338-42.

Eckert LB, Repasky GA, Ulku AS, McFall A, Zhou H, Sartor CI, et al. Involvement of ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res. 2004;64(13):4585- 92. https://doi.org/10.1158/0008-5472.can-04-0396 PMid:15231670

Baum JE, Sung KJ, Tran H, Song W, Ginter PS. Mammary epithelial-myoepithelial carcinoma: Report of a case with HRAS and PIK3CA mutations by next-generation sequencing. Int J Surg Pathol. 2019;27(4):441-5. https://doi.org/10.1177/1066896918821182 PMid:30585117

Cree IA. Progress and potential of RAS mutation detection for diagnostics and companion diagnostics. Expert Rev Mol Diagn. 2016;16(10):1067-72. https://doi.org/10.1080/14737159.2016.1 221345 PMid:27494709

Pylayeva-Gupta Y. RAS oncogenes: Weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761-74. https://doi.org/10.1038/nrc3106 PMid:21993244

Bonnot E, Passot G. RAS mutation: Site of disease and recurrence pattern in colorectal cancer. Chin Clin Oncol. 2019;8(5):55. https://doi.org/10.21037/cco.2019.08.11 PMid:31597436

Spandidos DA, Karaiossifidi H, Malliri A, Linardopoulos S, Vassilaros S, Tsikkinis A, et al. Expression of ras Rb1 and p53 proteins in human breast cancer. Anticancer Res. 1992;12(1):81-9. PMid:1567185

Kazi A, Xiang S, Yang H, Chen L, Kennedy P, Ayaz M, et al. Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clin Cancer Res. 2019;25:5984-96. https://doi.org/10.1158/1078-0432.ccr-18-3399

Lee KH, Koh M, Moon A. Farnesyl transferase inhibitor FTI- 277 inhibits breast cell invasion and migration by blocking H-ras activation. Oncol Lett. 2016;12(3):2222-6. https://doi.org/10.3892/ol.2016.4837 PMid:27602167

Cox AD, Der CJ, Philips MR. Targeting RAS membrane association: Back to the future for anti-RAS drug discovery. Clin Cancer Res. 2015;21(8):1819-27. https://doi.org/10.1158/1078-0432.ccr-14-3214 PMid:25878363

Koh MS, Moon A. Activation of H-ras and Rac1 correlates with epidermal growth factor-induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells. Biochem Biophys Res Commun. 2011;406(1):25-9. https://doi.org/10.1016/j.bbrc.2011.01.092

Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: Current status and future perspectives. Nat Rev Clin Oncol. 2012;9(1):16-32. PMid:22124364

Zhang T, Li Q, Chen I, Luo Y, Fan Y, Xu B. Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer. Oncotarget. 2017;8(22):36750-60. https://doi.org/10.18632/oncotarget.13581 PMid:27902470

Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: Prognostic and predictive potential. Lancet Oncol. 2010;11(2):174-83. https://doi.org/10.1016/s1470-2045(09)70262-1 PMid:20152769

Yoshioka T, Hosoda M, Yamamoto M, Taguchi K, Hatanaka KC, Takakuwa E, et al. Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer. Breast Cancer. 2013;22(2):185- 91. https://doi.org/10.1007/s12282-013-0474-2 PMid:23645542

Shaikenov TE, Adekenov SM, Basset S, Trivedy M, Wolfinbarger L. Arglabin is a Novel Inhibitor of the Farnesylation of Ras Proteins. Kazakhstan: Reports of Ministry of Science, Academy of Sciences Republic of Kazakhstan; 1998. p. 64-75.

Zhumakayeva A, Rakhimov K, Sirota V, Arystan L, Madiyarov A, Adekenov S. Long-term results of combination therapy for locally advanced breast cancer. Georgian Med News. 2018;282:30-5. PMid:30358536

Zhumakayeva AM, Rakhimov KD, Omarova IM, Arystan LI, Adekenov SM. Experimental, clinical and morphological analysis of H-ras oncoproteins for locally advanced breast cancer. Open Access Maced J Med Sci. 2019;7(19):3153-7. https://doi.org/10.3889/oamjms.2019.708 PMid:31949508

Murugan AK, Grieco M, Tsuchida N. RAS mutations in human cancers: Roles in precision medicine. Semin Cancer Biol. 2019;59:23-35. https://doi.org/10.1016/j.semcancer.2019.06.007 PMid:31255772

Spandidos DA, Agnantis NJ. Human malignant tumors of the breast, as compared to their respective normal tissue, have elevated of the Harvey ras oncogene. Anticancer Res. 1984;4(4-5):269-72. PMid:6207764

Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet. 2007;44(8):481-4. https://doi.org/10.1136/jmg.2007.049346 PMid:17369502

von Lintig FC, Dreilinger AD, Varki NM, Wallace AM, Casteel DE, Boss GR. Ras activation in human breast cancer. Breast Cancer Res Treat. 2000;62(1):51-62. https://doi. org/10.1023/a:1006491619920 PMid:10989985

Kai K, Iwamoto T, Kobayashi T. Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f (-) quiescent cells. Oncogene. 2014;33(4):440-8. https://doi.org/10.1038/onc.2012.609 PMid:23376849

Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19-65. PMid:19595306

Karnoub AE, Weinberg RA. Ras oncogenes: Split personalities. Nat Rev Mol Cell Biol. 2008;9(7):517-31. https://doi.org/10.1038/nrm2438 PMid:18568040