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Basic science

4978 - Wild-type KRAS mediates growth inhibition and resistance to MEK inhibitors through dimerization with mutant KRAS in lung adenocarcinoma

Date

09 Sep 2017

Session

Basic science

Presenters

Chiara Ambrogio

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

C. Ambrogio1, J. Kohler1, Z. Zhou2, H. Wang3, R. Paranal1, M. Capelletti1, C. Caffarra1, S. Li1, Q. Lv3, D. Santamaria4, K.D. Westover2, P.A. Jänne1

Author affiliations

  • 1 Medical Oncology, Dana Farber Cancer Institute, 02215 - Boston/US
  • 2 Biochemistry And Radiation Oncology, University of Texas Southwestern Medical Center, 75390 - Dallas/US
  • 3 3school Of Life Science And Technology, Tongji University, 200092 - Shanghai/CN
  • 4 U1218, Action Laboratory, University of Bordeaux, INSERM, F-33600 - Pessac/FR
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Abstract 4978

Background

Mutations in KRAS are the most frequent RAS alterations in human cancers and the prevalent driver event in lung adenocarcinoma (LUAD). There are no effective targeted therapies for KRAS-driven LUAD and chemotherapy remains the standard of care. Small-molecule inhibitors of the MAPK pathway, one of the prominent downstream KRAS mediators, show minimal clinical activity either as single agents or in combination with chemotherapy. Recently, wild-type KRAS (KRASWT) was shown to enhance tumor fitness in KRAS mutant AML and CRC cell lines while concomitantly increasing sensitivity to MEK inhibition. We hypothesized that dimerization between KRAS proteins could be a key regulator for lung adenocarcinoma biology and determinant of treatment response.

Methods

To study the role of wild-type KRAS in the context of KRAS-driven cancer cells, we used genetically inducible models of KRAS loss of heterozigosity (LOH). We developed an isogenic KRASMUT inducible system that lacks endogenous HRas/NRas but harbors conditional CREERT2-controlled KRaslox alleles. Furthermore, we reconstituted KRASWT and dimerization-deficient KRASD154Q in KRAS-driven murine and human LUAD cell lines lacking the wild-type KRAS allele and evaluated the in vitro and in vivo impact on tumor progression and response to MEK inhibition.

Results

KRASWT decreased in vitro and in vivo fitness of human and murine KRAS mutant LUAD tumor cells. However, this phenotype was reverted upon MEK inhibition, with KRAS LOH cells being more sensitive than KRASWT expressing cells. Interestingly, both effects were dependent on wild-type/mutant KRAS dimerization and not observed with the dimerization-deficient KRASD154Q. We provide a mechanistic model of the ambivalent function of KRASWT, linking its tumor suppressor function with increased MEK inhibitor resistance through dimerization with mutant KRAS.

Conclusions

• KRASWT affects cellular fitness in KRAS-driven LUAD • KRASWT impairs response to MEK inhibitors in KRAS-driven LUAD • KRASWT inhibitory effect is dependent on dimerization with mutant KRAS • Impaired wild-type/mutant KRAS dimerization restores sensitivity to MEK inhibitors in vivo.

Clinical trial identification

Legal entity responsible for the study

Dana Farber Cancer Institute

Funding

Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT17-15)

Disclosure

J. Kohler: Received consultant honoraria from Boehringer Ingelheim for writing and publishing two review articles on afatinib and travel grants from Roche, Amgen and Lilly. K.D. Westover: Reports receiving a commercial research grant from Astellas Pharmaceuticals. P.A. Jänne: Stock Ownership: Gatekeeper Pharmaceuticals Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, ARIAD Pharmaceuticals, Merrimack Pharmaceuticals, Roche, Genentech, Loxo Oncology, Ignyta Research Funding: Astellas Pharma, AstraZeneca. All other authors have declared no conflicts of interest.

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