Abstract
Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.
| Original language | English |
|---|---|
| Pages (from-to) | 84675-84687 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 51 |
| DOIs | |
| Publication status | Published - 2016 |
Fingerprint
Keywords
- Bromodomain
- KRAS
- NSCLC
- OTX015 (MK-8628)
- SCLC
ASJC Scopus subject areas
- Oncology
Cite this
OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations. / Riveiro, Maria E.; Astorgues-Xerri, Lucile; Vazquez, Ramiro; Frapolli, Roberta; Kwee, Ivo; Rinaldi, Andrea; Odore, Elodie; Rezai, Keyvan; Bekradda, Mohamed; Inghirami, Giorgio; D'Incalci, Maurizio; Noel, Kay; Cvitkovic, Esteban; Raymond, Eric; Bertoni, Francesco.
In: Oncotarget, Vol. 7, No. 51, 2016, p. 84675-84687.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
AU - Riveiro, Maria E.
AU - Astorgues-Xerri, Lucile
AU - Vazquez, Ramiro
AU - Frapolli, Roberta
AU - Kwee, Ivo
AU - Rinaldi, Andrea
AU - Odore, Elodie
AU - Rezai, Keyvan
AU - Bekradda, Mohamed
AU - Inghirami, Giorgio
AU - D'Incalci, Maurizio
AU - Noel, Kay
AU - Cvitkovic, Esteban
AU - Raymond, Eric
AU - Bertoni, Francesco
PY - 2016
Y1 - 2016
N2 - Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.
AB - Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.
KW - Bromodomain
KW - KRAS
KW - NSCLC
KW - OTX015 (MK-8628)
KW - SCLC
UR - http://www.scopus.com/inward/record.url?scp=85007488397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007488397&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13181
DO - 10.18632/oncotarget.13181
M3 - Article
VL - 7
SP - 84675
EP - 84687
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 51
ER -