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Molecular Basis of Therapeutics

Introduction to Anti-Cancer Drug Resistance

Anti-cancer drug resistance is an intricate procedure that arise by changing in the drug targets. The major cause of failure of cancer treatment is the growth of drug resistance by cancer cells, which may cause reappearance of disease. Anti-cancer drug resistance may occur due to factors like genetic differences in an individual in tumour somatic cells. Drug resistance can be overcome by several strategies, such as DNA microarray, development of targeted therapies, and proteomics technology (Settleman, 2016). Moreover, cancer drug resistance can be acquired by many ways, such as multi-drug resistance, altering in drug metabolism, apoptosis suppression, enhancing DNA repair, epigenetic drug targets, and gene amplification. Cancer chemotherapy by multi-drug resistance (MDR) explains the capability of cancer cells to endure in contradiction of an extensive variety of anti-cancer drugs. Today, chemotherapy is been widely used for cancer treatment and 90% of chemotherapies fails while metastasis and incursion of cancers in response to drug resistance. However, by administering certain drugs during chemotherapy, majority of patients tumour cells will become resilient to the drug (Mansoori et al., 2017). Therefore, the drug resistance has been a serious issue in treatment of cancer. This report focusses on the outlined advent of anti-cancer drug resistance and potential new anti-cancer drug.

Advent of Anti-Cancer Drug Resistance

The active research in industries as well as academics come with the advent of anti-cancer drug development and medicine or drug design, that are precisely targeted for an individual. The primary motive of this method is to inhibit or control the proliferation of cancer cells. Arsenic is a traditionally used drug which can also work as a naturally occurring toxic compound. Among various kinds of arsenic drugs, arsenic trioxide is the most widely used anticancer drug worldwide. Arsenic trioxide (trivalent arsenite AsIII) is an extremely effective drug to treat low toxicity of acute promyelocytic leukemia and ultimately treat lung cancer. This drug has been invented initially as a Chinese medicine that is used as a therapeutic representative to treat various diseases including rheumatic diseases, and syphilis (Li et al. 2014). For thousands of years arsenic trioxide act as medicine to treat diseases. In 19th century, arsenic trioxide was used to cure chronic myelogenous leukemia (CML). Currently, it has been discovered to be the utmost active drug with minimum toxicity for treating acute promyelocytic leukemia. Various research has been carried out to examine the molecular mechanism of arsenic trioxide with anticancer effects in cancer as well as haematological malignancies (Ota et al., 2018).

Treatment of lung cancer by using this drug was recently accepted by U.S. FDA. Lung cancer is a serious risk to human wellbeing, which is recently found with the maximum male death rates due to cancer (Torre et al., 2016). According to various studies, arsenic trioxide has consistently showing its effect against solid tumors, lung cancer and pancreatic cancer (Huang & Zeng, 2019). In particular for lung cancer, arsenic trioxide has anti-cancer effects that includes the induction of cell death. Since arsenic trioxide applies an anticancer effect by facilitating cell death, researchers do hard work to expose the mechanisms of activation or apoptosis pathway signalling of arsenic trioxide activates in cancer cells (Walker et al., 2016).

Drug combination is an effective strategy to reduce the anti-cancer drug resistance while treating cancer. Arsenic trioxide may act as favourable drug when used with other molecular-targeted drugs, chemotherapies, and other anticancer therapeutics like radiation. Drugs like resveratrol, dihydroartemisinic, sulindac and transcription factor like TWIST1 are used in combination with arsenic trioxide to treat malignancy (Gu et al., 2016). Although arsenic trioxide can begin with multiple varied mechanisms to treat lung cancer, but its healthcare applications are inadequate because of the insensitivity of drug and adverse reactions due to high dosage of drug to patients of lung cancer (Abaza et al., 2017). After further investigation, arsenic trioxide is proved to have positive effects on cancer cell death. It has been further used as combination with other therapeutic or drugs to advance its anticancer outcome in different kind of cancers. As this assessment part is focusing on lung cancer, so for lung cancer reports suggest that collective arsenic trioxide-sulindac treatment encouraged cell death of human non-small cell lung cancer (Hong et al., 2014).

Potential New Anti-Cancer Drug

Neratinib is a potential new anti-cancer drug that is used for treatment of breast cancer. It is commonly found as tyrosine kinase inhibitor anticancer drug. In 2011, neratinib was initially discovered to treat breast cancer, and during July 2017, this drug was approved in United States by FDA. It is proved to be an adjuvant treatment for adults who suffer from early stages of overexpressed HER-2 breast cancer. In April 2020, a new drug capecitabine has been submitted to use in combination with neratinib, to treat HER2+ breast cancer. This act as third-line of treatment. Currently, neratinib is designated to be an orphan drug which is used to treat rare diseases like HER-2+ breast cancer with brain metastases (Nasrazadani & Brufsky, 2020). However, each drug has its own positive and negative effects while working in human body. Neratinib is also found to have some negative effects like diarrhoea, electrolyte imbalance, risk of liver damage, and dehydration. Diarrhoea is found to be highly affecting neratinib during its first cycle of treatment, and decrease the score of HR-QOL. To reduce these symptoms, it is recommended to not take this drug in combination with gastric acid reducing agents. Moreover, it can be used with capecitabine to treat adults having metastatic or advanced HER-2 positive breast cancer. Other than this, it can be used following adjuvant trastuzumab-based therapy (Kast et al., 2017).

Breast cancer has complex molecular heterogeneity due to which targeted therapies are developed to solve this complexity. In approximately 20-30% case of breast cancer, HER2 has been overexpressed that makes the disease more aggressive and increase the death rate of patient. Initially, as discussed earlier, chemotherapies and trastuzumab has been given to the patients for 12 months to fight with this disease (Lambertini et al., 2017). But there is need of new emergence treatment to deal with this, and reduce the mortality rates. This search led to the development of neratinib as a drug to treat early stage HER-2+ breast cancer among patients (Kourie et al., 2017). In the era of targeted therapies, HER-2 positive breast cancer can be effectively cured. However, trastuzumab therapy is found to increase the risk of CNS metastasis in HER2 positive breast cancer patients. The phosphorylation of HER-2 and HER-3 in breast cancer cell line can be decreased by help of neratinib drug. Another drug, named tucatinib, works similar as neratinib. This drug is also recently discovered and is under clinical trials. Overexpression of HER-2 breast cancer cell lines can be potentially inhibited by help of neratinib. This works similar as lapatinib which is a type of type II kinase inhibitor used to inhibit HER2 (Collins et al., 2019). Neratinib daily dose is as 240 mg recommended that can be maximum tolerated in early developmental studies. If the patient has third grade diarrhoea, then maximum tolerable dose can be 320 mg. Neratinib therapy can be given for 12 months to reduce the symptoms of early stage HER-2+ breast cancer in women (Martin et al., 2017).

Now the question arises that how neratinib works? Neratinib irreversibly bind to cysteine compound in ATP biding of HER1, HER2, HER4. This led to reduction of receptor phosphorylation and inhibit the downstream signalling and the pathways that regulates cell cycle. When the signalling and pathway get blocked, then it eventually led to cell cycle arrest and cell death. The limitation of cross talks between receptor in trastuzumab resistance mechanism can be overcome by help of neratinib (Luque-Cabal et al., 2016).

In United States, surgical resection or adjuvant therapy is used as a standard treatment for treating breast cancer at early stages. Those patients who are diagnosed with HER-2 positive disease, trastuzumab has been taken as the treatment process for them along with chemotherapy for at least 12 months. In spite of these clinical treatments and their improved outcomes, there is an issue of high recurrence rate which remains constant. To overcome this issue, neratinib comes into play. This is an orphan drug that has been developed as extended adjuvant therapy to treat HER-2+ breast cancer during early stages. This agent is irreversible in nature and its treatment can enhance primary endpoint of ExteNET study among women’s having symptoms of early-stage breast cancer with HER-2+ factor. Due to the safety and efficiency of neratinib, it was recently approved as an adjuvant treatment for early stage HER-2+ breast cancer patients who had gone through the trastuzumab therapy for last 1 year. It provides valuable treatment by reducing recurrence risk in patients (Dhillon, 2019).

References for Anti-Cancer Drug Resistance

Abaza, Y., Kantarjian, H., Garcia-Manero, G., Estey, E., Borthakur, G., Jabbour E, et al. (2017). Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood,129, 1275-1283.

Collins, D. M., Conlon, N. T, Kannan, S., et al. (2019). Preclinical characteristics of the irreversible Pan-HER kinase inhibitor neratinib compared with lapatinib: implications for the treatment of HER2-positive and HER2-mutated breast cancer. Cancers (Basel), 11(6).

Dhillon, S. (2019). Neratinib in early-stage breast cancer: A profile of its use in the EU. Clinical Drug Investigation, 39, 221–229. doi: 10.1007/s40261-018-0741-2

Gu, S., Chen, C., Jiang, X., & Zhang, Z. (2016). Study on the resveratrol and arsenic trioxide combination induced apoptosis and its mechanism on lung adenocarcinoma cells. Journal of Hygiene Research, 45(1), 87–92.

Hong, Z., Bi, A., Chen, D., Gao, L., Yin, Z., & Luo, L. (2014). Activation of hedgehog signaling pathway in human non-small cell lung cancers. Pathology and Oncology Research, 20(4), 917–22.

Huang, W., & Zeng, Y. C. (2019). A candidate for lung cancer treatment: arsenic trioxide. Clinical Translational Oncology, 21, 1115–1126. doi: 10.1007/s12094-019-02054-6

Kast, K., Schoffer, O., Link, T., et al. (2017). Trastuzumab and survival of patients with metastatic breast cancer. Archives of Gynaecology and Obstetrics, 296(2), 303–312.

Kourie, H. R., Rassy, E., Clatot, F., et al. (2017). Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib. OncoTargets and Therapy, 10, 3363–72.

Lambertini, M., Ponde, N. F., Solinas, C., et al. (2017). Adjuvant trastuzumab: A 10-year overview of its benefit. Expert Review of Anticancer Therapy, 17(1), 61–74.

Li, C., Sun, B. Q., & Gai, X. D. (2014). Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours. Clinical and Translational Oncology, 16(7), 593–8.

Luque-Cabal, M., Garcia-Teijido, P., Fernandez-Perez, Y., et al. (2016). Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clinical Medical Insights Oncology, 10(1), 21–30.

Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S., & Baradaran, B. (2017). The different mechanisms of cancer drug resistance: A brief review. Advanced Pharmaceutical Bulletin,7(3), 339-348. doi:10.15171/apb.2017.041

Martin, M., Holmes, F. A., Ejlertsen, B., et al. (2017). Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology, 18(12), 1688–700.

Nasrazadani, A., & Brufsky, A. (2020). Neratinib: The emergence of a new player in the management of HER2 breast cancer brain metastasis. Future Oncology,16(7), 247-254. doi:10.2217/fon-2019-0719

Ota, A., Wahiduzzaman, M., & Hosokawa, Y. (2018). Arsenic-based anticancer-combined therapy: Novel mechanism inducing apoptosis of cancer cells. Intech Open. doi: 10.5772/intechopen.74824.

Settleman J. (2016). Cancer: Bet on drug resistance. Nature, 529(7586), 289–90. doi: 10.1038/nature16863. 

Torre, L. A., Siegel, R. L., & Jemal, A. (2016). Lung cancer statistics. Advances in Experimental Medicine and Biology, 893, 1–19.

Walker, A. M., Stevens, J. J., Ndebele, K., & Tchounwou, P. B. (2016). Evaluation of arsenic trioxide potential for lung cancer treatment: Assessment of apoptotic mechanisms and oxidative damage. Journal of Cancer Science Therapy, 8(1), 1–9.

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