A Novel Combination Treatment Targeting BCL-X-L and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers

作者：Cho Sung Yup; Han Jee Yun; Na Deukchae; Kang Wonyoung; Lee Ahra; Kim Jooyoung; Lee Jieun; Min Seoyeon; Kang Jinjoo; Chae Jeesoo; Kim Jong Il; Park Hansoo^*; Lee Won Suk^*; Lee Charles^*

来源：Molecular Cancer Therapeutics, 2017, 16(10): 2178-2190.

DOI：10.1158/1535-7163.MCT-16-0735

Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited. KRAS and BRAF mutations are prevalent genetic alterations in colorectal cancers, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCLXL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup.

• 出版日期2017-10