Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer
Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually ac...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | Cancer Biology & Therapy |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15384047.2023.2246208 |
| _version_ | 1797404016009805824 |
|---|---|
| author | Yoon Sun Park Joseph kim Yea Seong Ryu Jai-Hee moon Yu Jin shin Jeong Hee kim Seung-Woo hong Soo-A jung Seul lee Seung-Mi kim Dae Hee lee Do Yeon kim Hyeseon yun Ji-Eun you Dong Il yoon Chul Hee kim Dong-In koh Dong-Hoon jin |
| author_facet | Yoon Sun Park Joseph kim Yea Seong Ryu Jai-Hee moon Yu Jin shin Jeong Hee kim Seung-Woo hong Soo-A jung Seul lee Seung-Mi kim Dae Hee lee Do Yeon kim Hyeseon yun Ji-Eun you Dong Il yoon Chul Hee kim Dong-In koh Dong-Hoon jin |
| author_sort | Yoon Sun Park |
| collection | DOAJ |
| description | Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients. |
| first_indexed | 2024-03-09T02:46:59Z |
| format | Article |
| id | doaj.art-1768709d29094b5387a1c7c373462d07 |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-09T02:46:59Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-1768709d29094b5387a1c7c373462d072023-12-05T15:58:14ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762023-12-0124110.1080/15384047.2023.22462082246208Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancerYoon Sun Park0Joseph kim1Yea Seong Ryu2Jai-Hee moon3Yu Jin shin4Jeong Hee kim5Seung-Woo hong6Soo-A jung7Seul lee8Seung-Mi kim9Dae Hee lee10Do Yeon kim11Hyeseon yun12Ji-Eun you13Dong Il yoon14Chul Hee kim15Dong-In koh16Dong-Hoon jin17Asan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterAsan Medical CenterUniversity of Ulsan College of MedicineSignificant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.http://dx.doi.org/10.1080/15384047.2023.2246208pim1pik3camutant krascolorectal cancerpredictive marker |
| spellingShingle | Yoon Sun Park Joseph kim Yea Seong Ryu Jai-Hee moon Yu Jin shin Jeong Hee kim Seung-Woo hong Soo-A jung Seul lee Seung-Mi kim Dae Hee lee Do Yeon kim Hyeseon yun Ji-Eun you Dong Il yoon Chul Hee kim Dong-In koh Dong-Hoon jin Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer Cancer Biology & Therapy pim1 pik3ca mutant kras colorectal cancer predictive marker |
| title | Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer |
| title_full | Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer |
| title_fullStr | Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer |
| title_full_unstemmed | Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer |
| title_short | Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer |
| title_sort | mutant pik3ca as a negative predictive biomarker for treatment with a highly selective pim1 inhibitor in human colon cancer |
| topic | pim1 pik3ca mutant kras colorectal cancer predictive marker |
| url | http://dx.doi.org/10.1080/15384047.2023.2246208 |
| work_keys_str_mv | AT yoonsunpark mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT josephkim mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT yeaseongryu mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT jaiheemoon mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT yujinshin mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT jeongheekim mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT seungwoohong mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT sooajung mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT seullee mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT seungmikim mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT daeheelee mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT doyeonkim mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT hyeseonyun mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT jieunyou mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT dongilyoon mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT chulheekim mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT donginkoh mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer AT donghoonjin mutantpik3caasanegativepredictivebiomarkerfortreatmentwithahighlyselectivepim1inhibitorinhumancoloncancer |