A FAM83A Positive Feed-back Loop Drives Survival and Tumorigenicity of Pancreatic Ductal Adenocarcinomas

Abstract

Pancreatic ductal adenocarcinomas (PDAC) are deadly on account of the delay in diagnosis and dearth of effective treatment options for advanced disease. The insurmountable hurdle of targeting oncogene KRAS, the most prevalent genetic mutation in PDAC, has delayed the availability of targeted therapy for PDAC patients. An alternate approach is to target other tumour-exclusive effector proteins important in RAS signalling. The Family with Sequence Similarity 83 (FAM83) proteins are oncogenic, tumour-exclusive and function similarly to RAS, by driving the activation of PI3K and MAPK signalling. In this study we show that FAM83A expression is significantly elevated in human and murine pancreatic cancers and is essential for the growth and tumorigenesis of pancreatic cancer cells. Elevated FAM83A expression maintains essential MEK/ERK survival signalling, preventing cell death in pancreatic cancer cells. Moreover, we identified a positive feed-forward loop mediated by the MEK/ERK-activated AP-1 transcription factors, JUNB and FOSB, which is responsible for the elevated expression of oncogenic FAM83A. Our data indicates that targeting the MEK/ERK-FAM83A feed-forward loop opens up additional avenues for clinical therapy that bypass targeting of oncogenic KRAS in aggressive pancreatic cancers.

Systematic Analysis of Expression Profiles and Prognostic Significance for FAM83 Family in Non-small-Cell Lung Cancer

“…FAM83A has been reported to play a role in promoting cancer and reducing drug sensitivity in a variety of cancer ( Liu et al, 2020 ). Parameswaran et al (2019) indicated that FAM83A was overexpressed in human and murine pancreatic cancers and protected from cell death in pancreatic cancer cells by activating essential MEK/ERK survival signaling. Similarly, a study on breast cancer found that overexpression of FAM83A also enhanced cell proliferation and invasiveness, while increasing resistance to tyrosine kinase inhibitors (TKIs).…”

<p>miR-613 Suppresses Chemoresistance and Stemness in Triple-Negative Breast Cancer by Targeting FAM83A</p>

“…Previous studies indicated that FAM83A expression was elevated and served as an oncogene in several types of cancers such as breast cancer, pancreatic cancer, and hepatocellular cancer. 18,19 FAM83A is amplified and promotes cancer stem cell-like traits in pancreatic cancer. 20 Meanwhile, long non-coding RNA FAM83A-AS1 could help to stabilize FAM83A mRNA, suggesting the post-transcriptional regulation.…”

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

“…4,5 Mutations in KRAS constitutively activate its downstream signaling pathways 6 such as MEK/ERK, a mitogen-activated protein kinase (MAPK) pathway, this is known to promote cancer cell survival and chemoresistance. 7,8 KRAS mutations correlate significantly to poor therapeutic response in NSCLC patients. [9][10][11] Therefore, it is essential to develop novel KRAS-targeting drugs for treating recalcitrant NSCLC patients with KRAS mutations.…”