Prolonged MEK inhibition leads to acquired resistance and increased invasiveness in KRAS mutant gastric cancer

Journal Article · Sat Dec 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.11.030· OSTI ID:23134044

Choi, Kyoung-Min; Cho, Eunji ^[1]; Kim, Eunjung ^[2]; Shin, Jong Hwan; Kang, Minju; Kim, Boram ^[1]; Han, Eun Hee; Chung, Young-Ho ^[3]; Kim, Jae-Young ^[1]

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1. Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34134 (Korea, Republic of)
2. Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 (United States)
3. Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju, 28119 (Korea, Republic of)

Highlights: • MAPK pathway is important for the survival of KRAS mutant gastric cancer cells. • Prolonged MEK inhibition leads to acquired resistance. • c-MET activity is upregulated in MEK inhibitor resistant gastric cancer cells. • MEK inhibitor resistant gastric cancer cells harbor more invasive phenotype. • The increased invasiveness is abrogated by c-MET TKI or PI3K/mTOR dual inhibitor. Gastric cancer (GC) is one of the most common causes of cancer-associated death. However, traditional therapeutic strategies have failed to significantly improve the survival of patient with advanced GC. While KRAS mutations have been found in some patients with gastric cancer, an effective therapy to treat KRAS-driven gastric cancer has not been established yet. To provide a rationale for clinical application of kinase inhibitors targeting RAS pathways, we first determined the sensitivity of GC cell lines harboring KRAS mutations or amplification to RAS pathway inhibitors. We found that MAPK pathway inhibitors (MEKi and ERKi) were more effective than AKT inhibitor, suggesting that KRAS-driven gastric cancer cells are dependent on MAPK pathway for survival. Further, we established a KRAS mutant GC cell line with acquired resistance to MEK inhibitors in order to mimic clinical situation of kinase inhibitor resistance. A comprehensive analysis of tyrosine phosphorylation in receptor tyrosine kinases in combination with small molecule chemical library screening revealed upregulated c-MET phosphorylation in this resistance cell line with elevated sensitivity to c-MET TKI (crizotinib) and PI3K/mTOR dual inhibitor (BEZ235). We also showed that migration and invasion of resistant cells were promoted, and crizotinib and BEZ235 could inhibit this malignant phenotype. Overall, our results indicate that prolonged MAPK pathway inhibition could result in acquired resistance which is associated with increased malignant phenotype in KRAS mutant GC and pharmacological targeting c-MET and PI3K/mTOR could overcome this problem.

• OSTI ID: 23134044
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1-4 Vol. 507; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
NEOPLASMS
PHENOTYPE
PHOSPHORYLATION
RECEPTORS
THERAPY
TYROSINE