Weiwen Long, PhD

Weiwen Long, PhD

Institution: Wright State University

Project: Potential Therapeutic Target for Lung Adenocarcinoma with KRAS Mutations

Grant(s): Lung Cancer Discovery Award

We have overcome the challenges under the COVID 19 pandemic and overall have been able to conduct experiments and accomplish the proposed work. We have found that FBXL16, the protein of our interest, plays important roles in upregulating the oncogenic Akt/mTOR signaling and promotes lung adenocarcinoma cell growth and invasiveness. We also have been studying the role of FBXL16 in the development and progression of lung adenocarcinoma in mouse models. Dr. Marion Morel, a postdoctor in my lab and the co-Investigator of this ALA Lung Cancer Discovery Award, attended the AACR annual conference 2022 (April 8-13 in New Orleans) and presented the work supported by this award. The poster presentation is entitled “The F-box protein FBXL16 upregulates IRS1-PI3K-mTOR signaling in lung adenocarcinomas with KRAS mutations”. In addition, we have mentored Madison Alexander, an Honors program undergraduate/pre-med student, who participated in this project and presented her interesting finding as a poster titled “Depletion of the F-box protein FBXL16 increases apoptosis and sensitizes lung cancer cells to drugs targeting MEK or KRAS mutants” in Wright State University’s Festival of Research (October 8, 2021). Upon the renewal of this ALA Lung Cancer Discovery Award, we are confident that we are capable of performing the proposed experiments and accomplishing research aims, thereafter elucidating the role of FBXL16 in promoting lung adenocarcinoma growth and progression. Our long-term goal is to define FBXL16 as a novel prognostic marker and/or a therapeutic drug target for treating lung adenocarcinomas, particularly those with activating KRAS mutations.

Update: We have found that FBXL16 is selectively upregulated in lung adenocarcinoma (LUAD) cell lines expressing oncogenic KRas mutants (LUAD-KRas Mt). Depletion of FBXL16 led to decrease in phosphorylations of Akt, mTOR, S6K and S6, mainly due to the reduction of expression levels of multiple essential components of Akt/mTOR signaling pathway, including IR, IGFR and mTOR. Downregulation of Akt/mTOR signaling upon FBXL16 knockdown greatly suppressed LUAD cell growth, anchorage-independent colony formation in soft agar and invasiveness. FBXL16 positively regulates the stability of these proteins by antagonizing the activities of other F-Box protein E3 ligases, such as FBW7. In addition, we have found that depletion of FBXL16 greatly enhanced the efficacy of KRasG12C inhibitor or MEK inhibitor in suppressing growth of LUAD-KRas Mt cells. We are currently investigating the role of FBXL16 in LUAD development and progression using both xenograft tumor mouse models and transgenic FBXL16 knock in and KRasG12D knock-in mice.

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