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

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.

The integrated stress response in the induction of mutant KRAS lung carcinogenesis: Mechanistic insights and therapeutic implications

“…[13] In addition, inhibition of eIF2α-P in mice bearing a heterozygous germlineeIF2α S52A mutation substantially decreased the formation of mutant KRAS lung tumors in response to treatment with the carcinogen urethane. [13] Analysis of the pathway leading to eIF2α-P in mutant KRAS lung tumors identified a major role of the eIF2α kinase PERK in the process.…”

“…It has been recently demonstrated that the pro-survival role of PERK-eIF2α-P arm is crucial for the stimulation of growth of tumors with KRAS mutations in mouse LUAD models. [13] Specifically, ultrasound imaging [14] and immunohistochemical (IHC)…”

“…[13] Polysome profiling and RNA-seq analyses of the lung tumors identified a role of eIF2α-P in the translational repression of the dual-specificity phosphatase DUSP6, which inactivates ERK by dephosphorylation (Figure 2). [13] Tumors cells deficient in eIF2α-P exhibited elevated DUSP6 and decreased phosphorylated ERK compared to lung tumors with intact eIF2α-P. [13] Genetic inactivation of DUSP6 restored ERK phosphorylation and increased the growth of lung tumors with impaired eIF2α-P compared to tumors with intact eIF2α-P. [13] Pharmacological inhibition of the PERK-eIF2α-P arm by treatment with either a PERK kinase inhibitor or the integrated stress response inhibitor (ISRIB), a small molecule antagonist of the translational effects of eIF2α-P, [15] significantly inhibited the growth of mutant KRAS lung tumors in immune-deficient as well as immune-competent mice. [13] Collectively the findings supported the tumorigenic function of ISR as well as the therapeutic potential of ISR inhibitors in LUAD treatment.…”

“…[13] Tumors cells deficient in eIF2α-P exhibited elevated DUSP6 and decreased phosphorylated ERK compared to lung tumors with intact eIF2α-P. [13] Genetic inactivation of DUSP6 restored ERK phosphorylation and increased the growth of lung tumors with impaired eIF2α-P compared to tumors with intact eIF2α-P. [13] Pharmacological inhibition of the PERK-eIF2α-P arm by treatment with either a PERK kinase inhibitor or the integrated stress response inhibitor (ISRIB), a small molecule antagonist of the translational effects of eIF2α-P, [15] significantly inhibited the growth of mutant KRAS lung tumors in immune-deficient as well as immune-competent mice. [13] Collectively the findings supported the tumorigenic function of ISR as well as the therapeutic potential of ISR inhibitors in LUAD treatment. [13]…”

The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress

“…At the interfaces of cellular proliferation, apoptosis, survival, and protein synthesis, the ISR has naturally emerged as an area of interest in cancer research. Although studies on the role of the ISR in cancer have been conflicting, the notion that the ISR is protective for cancer cells has gained traction in recent years ( Ghaddar et al, 2021 ; Koromilas, 2015 ). This is in line with the observation that cancer cells experience hostile microenvironments characterized by nutrient deprivation and low oxygen availability.…”