The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

Nour Ghaddar,Shuo Wang,Ola Larsson,John Le Quesne,Massimo Broggini,Maria Hatzoglou,Nicolas Ah-Son,Jothilatha Krishnamoorthy,Cedric Darini,Bethany Woodvine,Helmuth Popper,Antonis E Koromilas,Koren K Mann,Leah Officer,Ana Teodósio,Ivan Topisirovic,Vincent Van Hoef,Urszula Kazimierczak,Myriam Johnson

doi:10.1038/s41467-021-24661-0

Abstract

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.

Highlights

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis
Adopting tissue microarrays (TMAs) derived from a continuous cohort of 928 primary human lung adenocarcinoma (LUAD) we obtained data showing that patients positive for p-eIF2α have a significantly poorer outcome compared to patients negative for p-eIF2α (Fig. 1a, b; Supplementary Fig. 1)
The clinical relevance of our findings is supported by the examination of a large cohort of 928 archival primary human LUADs, which revealed that p-eIF2α is elevated in a way that correlates with local invasiveness, with high-risk tumor subtypes, and with tumor cell proliferation (Fig. 1; Supplementary Fig. 1)

Summary

Introduction

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). In addition to PERK, ISR consists of three other kinases, namely, the hemeregulated kinase HRI, the general control nonderepressible GCN2, and the RNA-activated protein kinase PKR, which exhibit high specificity for the phosphorylation of the alpha (α) subunit of the eukaryotic translation initiation factor 2 at serine 52 (peIF2α) in response to distinct forms of stress. Our findings demonstrate the tumorigenic function of the PERK/p-eIF2α arm of ISR together with the strong therapeutic benefits of its pharmacological inhibition for the treatment of mutant KRAS lung cancer. Because mutant KRAS cancers are largely refractory to therapy[14], our data show that the adaptive role of ISR in the addiction of tumors to KRAS mutations is a rational target for the implementation of effective therapies against a deadly form of lung cancer

Methods

Results

Conclusion