Sohum Purao

Background: Cancer causes 1/6 deaths worldwide and is the 2^nd in causes of death globally¹. Despite many advances in cancer in the many decades, chemotherapy continues to be the most common treatment for individuals with cancer. However, chemotherapy comes with its own costs; one in particular that an incredible amount of patients have been grappling with is multi drug resistance. It is extremely common for cells undergoing multiple rounds of chemotherapeutic treatment to develop MDR for various reasons despite the utilization of cocktails. In fact, drug resistance accounts for 90% of mortality in cancer patients³. MDR can result from many mechanisms; however, this study will focus on the increased drug efflux of cells lowering intracellular drug concentrations. Targeted therapies against tyrosine kinases, nuclear receptors, and other molecular targets are now emphasized compared to the last 50 years’ surgery and polychemotherapeutic approaches. Despite this, no FDA approved drug exists today to combat MDR². Tyrosine kinase inhibitors have shown some promise and thus, further findings could suggest new therapeutics to combat the treatment for MDR⁵.

Objective: In this narrative review, we explored the drug Sitravatinib and the various mechanisms in which MDR is inhibited through ABC transporter inhibition.

Search Methods: An online search in PubMed database was conducted from 2019 to 2024 using the following keywords: “multi-drug resistance”, “ABC transporter proteins”, “tyrosine kinase inhibitors”.

Results: Studies solidified the major role of ABC transporters in MDR by the treatment of anti-cancer therapeutics decreasing ABC overexpression significantly in ovarian cancer cells⁶. Specifically, studies showed that ABCB1 and ABCG2 were the transporters most linked to poor prognosis in patients with lung, breast, ovarian and many other cancers. A potential ABC transporter inhibition mechanism was through tyrosine kinase inhibition⁶. Inhibiting this tyrosine kinase phosphorylation cascade was tested by utilizing different drugs and examining their effects on various cancer cells⁴. SKLB610 was a repurposed tyrosine kinase inhibitor that was sensitive to ABCG2 overexpressing cancer cells but not ABCB1 cells⁷. Effect of Topotecan (chemotherapeutic agent) was found significantly greater in ABCG2-overexpressing cancer cells that were treated with SKLB610, portraying its reversal of MDR in only ABCG2-overexpressing cells⁷. However, Sitravatinib induced apoptosis and allowed increased influx of chemotherapeutic drugs for both cells overexpressing ABCB1 and ABCG2 transporters, portraying this tyrosine inhibitor’s ability to block both major ABC transporters involved in MDR⁷.

Conclusion: Studies have found that inhibition of the tyrosine kinase phosphorylation cascade that is imperative for ABC transporter protein function has yielded great success in reversing MDR⁶. Specifically, Sitravatinib has shown promise in inhibiting two major ABC transporter proteins (ABCB1 and ABCG2) by re-sensitizing cells overexpressing these transporters to anti-cancer substrates (chemotherapeutic drug) through drug-mediated apoptosis². This drug poses as a potential drug to combat MDR; however, further studies must be done to examine its mechanistic effects on other pathways as well as animals.

Works Cited:

1. Bukowski K, Kciuk M, Kontek R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int J Mol Sci. 2020;21(9):3233. Published 2020 May 2. doi:10.3390/ijms21093233
2. Wu CP, Hung CY, Hsieh YJ, et al. ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines. Cells. 2023;12(7):1056. Published 2023 Mar 30. doi:10.3390/cells12071056
3. Wu CP, Hsiao SH, Huang YH, et al. Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs. Cancers (Basel). 2020;12(1):195. Published 2020 Jan 13. doi:10.3390/cancers12010195
4. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575(7782):299-309. doi:10.1038/s41586-019-1730-1
5. Wang J, Seebacher N, Shi H, Kan Q, Duan Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017 Jul 12;8(48):84559-84571. doi: 10.18632/oncotarget.19187. PMID: 29137448; PMCID: PMC5663620.
6. Wang Y, Wang Y, Qin Z, et al. The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer. Expert Opin Drug Metab Toxicol. 2021;17(3):291-306. doi:10.1080/17425255.2021.1887139
7. Dean M, Moitra K, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Hum Mutat. 2022;43(9):1162-1182. doi:10.1002/humu.24418