Cracking the code of drug resistance

By Caleb Yi

According to the National Cancer Institute, almost 90% of cancer-related deaths are linked to the same thing: drug resistance. And despite all the new treatments and developments we have, tumors continue to adapt, evade, and return stronger than ever. But it isn’t all bad news, because scientists are now employing the latest biological techniques to outsmart cancer and fight back. 

Drug resistance matters because it’s the main reason that cancer treatments stop working. And when treatments stop working, the disease can become extremely dangerous, growing unchecked, and spreading to new parts of the body. This happens when, under the pressure of chemotherapy, targeted drugs, or immunotherapy, most cancer cells die, but the few that survive live on to adapt and multiply. These surviving cells can now combat the techniques that were once used to kill them, creating drug resistance. But there is hope, with many new techniques and technologies on the horizon.

Extrachromosomal DNA, or ecDNA for short, is a DNA fragment that is found outside of normal chromosomes. The problem with them lies in the fact that they don’t follow the standard inheritance of normal chromosomes, which causes them to replicate chaotically and unevenly when they divide. They also often carry cancer-promoting genes and can fuel tumor growth and accelerate treatment resistance. When drug resistance happens because cancer cells evolve faster than treatments, ecDNA poses a large issue due to it supercharging that process. Essentially, it can be shuffled, multiplied, or lost - thus creating diversity at a rapid pace. But we can combat this with its largest vulnerability, which is replication that is dependent on repair proteins like CHK1. So in these ecDNA heavy tumors, scientists can use CHK1 inhibitors, which are small molecules that block CHK1’s activity, and without the CHK1, the cancer cells don’t pause for repair. This leads to unrepaired DNA damage and selective cell death. The main inhibitors are prexasertib, SRA737, and MK-8776, making bounds in stopping the ecDNA. This is extremely exciting for drug resistance because, traditionally, ecDNA is resistant to targeted therapies as it bypasses drugs. Targeting the CHK1 addresses the arms race entirely and prevents the problems that ecDNA creates. 

Another response to drug resistance comes from nature itself, in the form of venom-inspired peptides. These small molecules are derived from animal venom, namely spiders, scorpions, snakes, and horseshoe crabs, have evolved to target cell membranes and proteins. A preclinical study published by Elsevier from Pharmacological Research shows the promise of this new breakthrough, when modified peptides from a Brazilian tarantula and Japanese horseshoe crab killed melanoma cells. This included cells that were resistant to most other treatments. One of the greatest things about these peptides is that cancer cells cannot develop resistance because they target the tumor cell membrane, leaving no room for adaptation to combat this strategy. Another study on spider venom peptides shows that lycosin-I, a new peptide, caused over 90% tumor cell death in many different human cancer lines. Not only were they extremely effective for tumor cells, but they also showed a low effect on normal cells. So with venom-inspired peptides, we can bypass the common resistance mechanisms by attacking cancer cell membranes, work against resistant and dormant cells, and have a low chance of resistance development. 

 Drug resistance still stands as one of cancer’s greatest obstacles. But it isn’t as unsolvable as we once imagined. With research evolving faster than ever, we are finally able to get to the heart of the problem. From exposing ecDNA’s weaknesses to utilizing venoms from nature to create peptides, the road ahead is bright. Though it will take rigorous testing, time, and many trials, the new innovations in cancer research show great promise.

Works Cited

American Association for Cancer Research. “Abstract 1626: Tumors Driven by Oncogene-Amplified Extrachromosomal DNA Are Dependent on CHK1.” Cancer Research, vol. 83, no. 7 Suppl, 2023. AACR Journals, https://aacrjournals.org/cancerres/article/83/7_Supplement/1626/722133/Abstract-1626-Tumors-driven-by-oncogene-amplified.

King, Caroline, et al. “CHK1 Inhibition in Cancer Therapy: Perspectives and Progress.” Cancers, vol. 13, no. 5, 2021, p. 1192. MDPI, https://doi.org/10.3390/cancers13051192.

Mahadevappa, R., et al. “Venom Peptides as Anti-Cancer Agents: Recent Advances.” International Journal of Molecular Sciences, vol. 22, no. 23, 2021, p. 13286. PubMed, https://pubmed.ncbi.nlm.nih.gov/33276098/.

National Cancer Institute. “Drug Resistance and Cancer.” National Cancer Institute, https://www.cancer.gov/about-cancer/treatment/research/drug-resistance. Accessed 30 Aug. 2025.

Nathanson, David A., et al. “Extrachromosomal DNA in Cancer: Structures, Functions, and Mechanisms.” Nature Reviews Cancer, vol. 22, 2022, pp. 627–42. PubMed, https://pubmed.ncbi.nlm.nih.gov/35609926/.

Velloso, F., et al. “Peptides Derived from Brazilian Tarantula and Japanese Horseshoe Crab Show Anti-Melanoma Potential.” Pharmacological Research, 2024. Elsevier. Reported in MedicalXpress, https://medicalxpress.com/news/2024-12-horseshoe-crab-tarantula-derived-peptides.html.

Verhaak, Roel G. W., et al. “Origins and Impact of Extrachromosomal DNA in Cancer.” Nature Reviews Genetics, 2024. PubMed, https://pubmed.ncbi.nlm.nih.gov/39506150/.

Zhang, Yuanyuan, et al. “Lycosin-I, a Spider Venom Peptide, Induces Apoptosis in Human Cancer Cells.” Frontiers in Oncology, vol. 9, 2019, p. 1163. PubMed Central, https://pmc.ncbi.nlm.nih.gov/articles/PMC6551028/.