Key roles of EMT for adaptive resistance to MEK inhibitor in KRAS mutant lung cancer

ABSTRACT KRAS is frequently mutated in a variety of cancers including lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with MEK inhibitors is relatively ineffective. One major contributor to limited efficacy is attributed to the reactivation of MAPK signal following MEK inhibition by multiple feedback mechanisms. In a recent study, we have identified that epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling following MEK inhibition in KRAS mutant lung cancer. In epithelial-like cells, this feedback was mediated by ERBB3. In contrast, in mesenchymal-like cells, the feedback was attributed to the fibroblast growth factor receptor 1 (FGFR1) pathway. FGFR1 was dominantly expressed in mesenchymal-like cells: suppression of SPRY proteins by MEK inhibition relieved negative feedback control of basal FGFR-FRS2 function, resulting in reactivation of MAPK signaling via FGFR1. Therapeutically, the combination of MEK inhibitor trametinib with an FGFR inhibitor induced tumor regressions in tumor xenografts derived from mesenchymal-like KRAS mutant cancer cell lines as well as a patient derived xenograft model with a representative mesenchymal phenotype. Collectively, feedback activation of MAPK by FGFR1 signaling mitigates the effect of MEK inhibitor in mesenchymal-like KRAS mutant lung tumors, and combinations of clinically available FGFR1 inhibitors and MAPK inhibitors constitute a therapeutic approach to treat these cancers effectively.

[1]  M. Nishimura,et al.  Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer. , 2016, Cancer discovery.

[2]  K. Dutta,et al.  A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling , 2016, Cell.

[3]  Yi Liu,et al.  Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. , 2016, Cancer discovery.

[4]  U. McDermott,et al.  Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination , 2016, Cancer cell.

[5]  Neal Rosen,et al.  Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism , 2016, Science.

[6]  E. Petricoin,et al.  Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. , 2016, Cancer cell.

[7]  Stephen T. C. Wong,et al.  EMT is not required for lung metastasis but contributes to chemoresistance , 2015, Nature.

[8]  V. LeBleu,et al.  EMT Program is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer , 2015, Nature.

[9]  S. Cook,et al.  MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road , 2015, Nature Reviews Cancer.

[10]  G. Gibney,et al.  Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS‐mutant melanoma , 2014, Pigment cell & melanoma research.

[11]  S. Fesik,et al.  Drugging the undruggable RAS: Mission Possible? , 2014, Nature Reviews Drug Discovery.

[12]  Andreas Schlicker,et al.  Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. , 2014, Cell reports.

[13]  D. Esposito,et al.  Dragging ras back in the ring. , 2014, Cancer cell.

[14]  A. Bardelli,et al.  Climbing RAS, the everest of oncogenes. , 2014, Cancer discovery.

[15]  Shuxia Zhao,et al.  Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. , 2013, Cancer discovery.

[16]  F. McCormick,et al.  Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. , 2013, Cancer discovery.

[17]  Carlotta Costa,et al.  MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. , 2012, Cancer research.

[18]  Jian Jin,et al.  Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer , 2012, Cell.

[19]  Min Yu,et al.  TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers , 2012, Cell.

[20]  David B Solit,et al.  Targeting the Mitogen-Activated Protein Kinase Pathway: Physiological Feedback and Drug Response , 2010, Clinical Cancer Research.

[21]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[22]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[23]  E. Neilson,et al.  Biomarkers for epithelial-mesenchymal transitions. , 2009, The Journal of clinical investigation.