205P - Identification of novel bypasses of KRAS addiction

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Biomarkers
Colon and Rectal Cancer
Rectal Cancer
Presenter Seav Huong Ly
Citation Annals of Oncology (2016) 27 (suppl_9): ix53-ix67. 10.1093/annonc/mdw581
Authors S.H. Ly1, E.B. Krall2, W.C. Hahn2
  • 1Division Of Medical Sciences, Harvard University, 02115 - Boston/US
  • 2Department Of Medical Oncology, Dana Farber Cancer Institute, 02115 - Boston/US

Abstract

Background

Oncogenic mutations of RAS are detected in approximately 30% of human cancers. KRAS is highly mutated in pancreatic, colorectal and lung cancers. Direct therapeutic targeting of Ras and its membrane association has been challenging due to high affinity of GTP to Ras and unexpected mechanism of alternative post-translational modification. While few inhibitors of downstream RAS effectors – MAPK and PI3K pathways – show some clinical efficacy, they are complicated by complex feedback loops, and as single agents are not effective in KRAS-mutant cancers. Combination therapies may be promising yet limited by narrow therapeutic window. Identification of alternative strategies to directly inhibiting RAS and MAPK/PI3K pathways is key to address this unmet need.

Methods

To this end, we performed a genome-scale open reading frames screen to identify genes capable of restoring viability to KRAS-dependent cells (HCT116) following KRAS suppression. One of the top hits included LIM homeobox 9 (LHX9), a homeobox family transcription factor essential for mouse gonad, limb, and brain development. While LHX9 is amplified in several cancers, little is known regarding its roles in cancers. We used hypothesis-driven and unbiased approaches including RNA-seq, ChIP-seq, and IP-mass spectrometry to investigate the basis of LHX9-mediated bypass of KRAS dependency.

Results

We showed that LHX9 could rescue KRAS suppression in vitro and in vivo. Moreover, LHX9 overexpression in KRAS-dependent cancer cell line was sufficient to form tumors in the absence of KRAS. LHX9 rescued KRAS suppression by at least three mechanisms. First, LHX9 reactivated MAPK and PI3K pathways. Second, LHX9 bound to promoters/enhancers and restored expression of genes including YAP1 which were downregulated by KRAS. Third, LHX9 increased expression and activation of genes including STAT3 whose regulation was independent of KRAS expression.

Conclusions

Here, we identified LHX9 as a novel bypass of KRAS addiction. Multiple unbiased approaches revealed at least three mechanisms by which LHX9 rescued KRAS suppression. Our findings contribute to the complex KRAS biology and further investigation may potentially highlight novel therapeutic targets for KRAS-dependent cancers.

Clinical trial indentification

Legal entity responsible for the study

Harvard University and Dana Farber Cancer Institute

Funding

USA National Institutes of Health

Disclosure

W.C. Hahn: WCH is a consultant for Novartis and receives grant support from Novartis. All other authors have declared no conflicts of interest.