Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

Lindsey Carlsen; Christoph Schorl; Kelsey Huntington; Liz Hernandez-Borrero; Aakash Jhaveri; Shengliang Zhang; Lanlan Zhou; Wafik S El-Deiry

doi:10.18632/oncotarget.28075

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

Oncotarget. 2021 Sep 28;12(20):2006-2021. doi: 10.18632/oncotarget.28075.

Authors

Lindsey Carlsen^{1

2

3

4}, Christoph Schorl^{2

5

6

7}, Kelsey Huntington^{1

2

3

4}, Liz Hernandez-Borrero^{1

2

3

4}, Aakash Jhaveri^{1

3}, Shengliang Zhang^{1

2

3

7}, Lanlan Zhou^{1

2

3

7}, Wafik S El-Deiry^{1

2

3

4

8

7}

Affiliations

¹ Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
² The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.
³ Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
⁴ Pathobiology Graduate Program, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
⁵ Department of Molecular Biology, Cell Biology and Biochemistry, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
⁶ Genomics Core Facility, Brown University, Providence, RI 02903, USA.
⁷ Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
⁸ Hematology-Oncology Division, Department of Medicine, Rhode Island Hospital and Brown University, Providence, RI 02903, USA.

Abstract

Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.

Keywords: 5-fluorouracil; chemotherapy mechanism; colon cancer; irinotecan; oxaliplatin.