2. Academic Validation
  3. MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors

MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors

  • Cancer Res. 2021 May 15;81(10):2714-2729. doi: 10.1158/0008-5472.CAN-20-2370.
Bin Yang  # 1,  Xi Li  # 1,  Yu Fu  # 1,  Ensong Guo 1,  Youqiong Ye 2,  Fuxia Li 1,  Si Liu 1,  Rourou Xiao 1,  Chen Liu 1,  Funian Lu 1,  Jia Huang 1,  Tianyu Qin 1,  Leng Han 2,  Guang Peng 3,  Gordon B Mills 4 5 6,  Chaoyang Sun 7,  Gang Chen 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
  • 2 Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas.
  • 3 Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4 Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
  • 5 Knight Cancer Institute, Portland, Oregon.
  • 6 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China. suncydoctor@gmail.com gumpc@126.com.
  • # Contributed equally.
PMID: 33589518 DOI: 10.1158/0008-5472.CAN-20-2370
Abstract

Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 Antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors. SIGNIFICANCE: This study provides key insights into the potential for using MEKi combined with PARPi and anti-PD-L1 for the treatment of all mutant KRAS tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.

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