Abstract
Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 4599-4610 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 37 |
| Issue number | 33 |
| DOIs | |
| Publication status | Published - Aug 16 2018 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. / Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi; Wang, Yi Jun; Misale, Sandra; Bardelli, Alberto; Yu, Jian; Zhang, Lin.
In: Oncogene, Vol. 37, No. 33, 16.08.2018, p. 4599-4610.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer
AU - Knickelbein, Kyle
AU - Tong, Jingshan
AU - Chen, Dongshi
AU - Wang, Yi Jun
AU - Misale, Sandra
AU - Bardelli, Alberto
AU - Yu, Jian
AU - Zhang, Lin
PY - 2018/8/16
Y1 - 2018/8/16
N2 - Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
AB - Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
UR - http://www.scopus.com/inward/record.url?scp=85046719905&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046719905&partnerID=8YFLogxK
U2 - 10.1038/s41388-018-0289-x
DO - 10.1038/s41388-018-0289-x
M3 - Article
C2 - 29755130
AN - SCOPUS:85046719905
VL - 37
SP - 4599
EP - 4610
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 33
ER -