MAPK1 p.D321N mutation confers sensitive to erlotinib in head and neck squamous cell carcinoma (HNSCC)
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AbstractThe annual incidence of head and neck squamous cell carcinoma (HNSCC) is ~0.88 million worldwide (IARC, WHO 2018). Despite great success of precision medicine in major cancers such as lung cancer and breast cancers, there are limited precision therapies for HNSCC. We previously reported an HNSCC patient whose tumor harbored a somatic MAPK1 p.E322K mutation demonstrating exceptional clinical response to erlotinib, an EGFR inhibitor. Subsequent laboratory investigation confirmed the ability of MAPK1 p.E322K to hyperactivate EGFR, thus causing erlotinib sensitivity in HNSCC models, both in vitro and in vivo. Here, we sequenced 105 tumors from Hong Kong (HK) HNSCC patients by next-generation sequencing (NGS) on MAPK1 gene and we found a 5.71% rate (6/105 tumors) of MAPK1 somatic mutation in HK-HNSCC. This rate appears to be relatively higher than the 1.75% (9/521 tumors) rate in the US-TCGA HNSCC cohort (P=0.0288). Apart from the MAPK1 p.E322K mutation found in the US-TCGA HNSCC cohort, we identified novel MAPK1 p.R135K and p.D321N mutations in our HK cohort which were absent in the US TCGA HNSCC. Pan-cancer mapping of MAPK1 somatic mutations revealed that MAPK1 p.R135K and p.D321N mutations are also recurrent hotspot mutation in TCGA pan-cancers (32 cancer types). Strikingly, based on the X-ray crystallography of the human MAPK1 protein, R135 and D321 amino acid residues both reside on the same kinase interaction motif (KIM) domain as E322 (all are within a 13Å distance in 3D). Thus, we further investigated if MAPK1 p.R135K and p.D321N mutations might function similarly as MAPK1 p.E322K mutant in terms of their abilities to drive HNSCC growth, and erlotinib sensitivity in HNSCC models. We employed the same FaDu retroviral infection method to study these mutations as we did previously, and we found that MAPK1 p.D321N (P<0.0001) was a driver for HNSCC proliferation, while MAPK1 p.R135K was not (all vs. MAPK1-wildtype). Subsequent in vivo erlotinib treatment experiments with xenografts bearing these mutants and MAPK1-wildtype showed that MAPK1 p.D321N tumors demonstrated heightened sensitivity to erlotinib with marked reduction of tumor size, tumor cell positivity, as well as membranous pEGFR expression when compared to vehicle treatment (P=0.0037). Whereas MAPK1 p.R135K tumors only showed a trend for erlotinib sensitivity (P=0.0646), with reduction in membranous p-EGFR expression by erlotinib in the tumors. Thus, MAPK1 p.D321N mutation confers erlotinib-sensitivity in HNSCC system. Further clinical investigation is warranted to further explore the relationship between various MAPK1 mutations and erlotinib sensitivity in HNSCC patients.
All Author(s) ListHoi Lam NGAN, Peony Hiu Yan POON, Yu-Xiong SU, Jason Yik Kuen CHAN, Kwok-Wai LO, Chun Kit YEUNG, Yuchen LIU, Eileen WONG, Hui LI, Chin Wang LAU, Wenying PIAO, Vivian Wai Yan LUI
Name of ConferenceAmerican Association for Cancer Research Annual Meeting 2020
Start Date of Conference27/04/2020
End Date of Conference28/04/2020
Place of ConferencePhiladelphia
Country/Region of ConferenceUnited States of America
Proceedings TitleCancer Research
Volume Number80
Issue NumberSuppl 16
LanguagesEnglish-United States

Last updated on 2022-16-01 at 23:41