In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3885-3885
Abstract:
The MAPK pathway is a major driver of malignant progression, particularly in cancers arising from mutations in pathway components, and BRAF and MEK inhibitors have been approved for treatment of BRAF-mutant melanoma. ERK1/2 kinases are the final node in the MAPK signaling pathway and offer the possibility of clinical benefit in settings where earlier drugs are ineffective. We have previously reported that KO-947, a potent and selective inhibitor of ERK1/2 with extended target residence time and favorable pharmaceutic properties, displays robust single-agent antitumor activity in PDX models of adenocarcinomas with RAS/RAF mutations, and in squamous cell carcinomas (SCCs) that lack mutations in MAPK pathway components. Here we report the discovery of a novel biomarker that is associated with sensitivity to KO-947 in head and neck SCC and esophageal SCC PDX models. Recurring amplification of chromosome 11 between bands q13.3 and q13.4 is a feature of several tumor types, including ESCC and HNSCC. TCGA reports incidence rates of & gt;50% in ESCC and ~20% in HNSCC, although higher frequencies are seen in some subtypes, such as pharyngeal and HPV-negative SCC. The 11q13 amplicon commonly contains about a dozen genes, including several potential oncogenes with functional linkage to the MAPK pathway, such as CCND1, FADD and the recently described calcium-dependent chloride channel ANO1. PDX campaigns were carried out in 24 ESCC and 18 HNSCC models, including 16 and 7 of each with 11q13 amplification, respectively. Groups of three animals were dosed with KO-947 at 300mg/kg QW, tumor growth was monitored for 3-6 weeks and responses were categorized as progressive disease, stable disease (SD, & gt;80% TGI) or partial/complete response (PR/CR, & gt;30% regression). In ESCC tumor-bearing animals, the overall response rates (ORR = PR+CR) were 33% in the overall population, 51% in the 11q13-amplified (11q-AMP) and 3% in 11q13-WT. The disease control rates (DCR = PR/CR+SD) were 54% overall, 77% in 11q-AMP and 21% in 11q-WT. In HNSCC tumor-bearing animals, the ORRs were 24% in the overall population, 56% in 11q-AMP and 9% in 11q-WT, with DCRs of 40%, 69% and 26% in the three subsets, respectively. 11q-AMP was significantly associated with response to KO-947 in both tumor types. ROC analysis defined the minimum effective copy number as 4 and revealed significant associations between expression levels of several 11q13 amplicon genes and response to KO-947. A key role for ANO1 in driving ERK-dependent tumor growth in 11q-AMP cases was further indicated by the observation that ANO1 expression was silenced in some 11q-AMP models and these tumors failed to respond the ERK inhibition. The results suggest that 11q13 amplification in SCCs can drive tumor growth and survival in a MAPK-dependent manner and that 11q-AMP may be a useful biomarker for predicting clinical response to ERK inhibitors. Citation Format: Francis J. Burrows, Linda Kessler, Tao Wu, Xin Gao, Jeffrey Chen, Rasmus Hansen, Shuangwei Li, Carol Thach, Shisheng Li, Ke Yu, Jeff Kucharski, Ulf Peters, Jun Feng, Yi Wang, Yvonne Yao, Ata Zarieh, Matt Janes, Jingchuan Zhang, Liansheng Li, Dana Hu-Lowe, Pingda Ren, Yi Liu. 11q13 amplification selects for sensitivity to the ERK inhibitor KO-947 in squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3885.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-3885
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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