In:
Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6662 ( 2023-09-08)
Abstract:
KRAS is one of the most frequently mutated genes in human cancer. Despite advances in the development of inhibitors that directly target mutant KRAS and the approval of KRAS G12C inhibitors sotorasib and adagrasib for the treatment of KRAS G12C -mutant non–small cell lung cancer (NSCLC) patients, multiple lines of clinical and preclinical evidence demonstrate that adaptive resistance to KRAS inhibitors (KRASi) is rapid and almost inevitable. The heterogeneous resistance mechanisms in patients and dose-limiting toxicity associated with targeting multiple KRASi resistance pathways—such as receptor tyrosine kinases (RTKs), extracellular signal–regulated kinase (ERK), and AKT–remain a major barrier to progress. RATIONALE Most cancers require a balanced protein homeostasis (proteostasis) network to maintain oncogenic growth. Therapeutic insults often disrupt proteostasis and induce proteotoxic stresses. Residual drug-tolerant cells must overcome imbalances in the proteostasis network to maintain survival. How a proteostasis network is orchestrated by driver oncogenes and the proteostasis reprogramming mechanisms that bypass oncogene addiction and allow for acquired resistance to targeted therapies remain largely unknown. In this study, we investigated the regulation of proteostasis by oncogenic KRAS and the rewiring of proteostasis network underlying the acquired resistance to KRAS inhibition. RESULTS We show that oncogenic KRAS is critical for protein quality control in cancer cells. Genetic or pharmacological inhibition of oncogenic KRAS rapidly inactivated both cytosolic and endoplasmic reticulum (ER) protein quality control machinery, two essential components of the proteostasis network, through inhibition of the master regulators heat shock factor 1 (HSF1) and inositol-requiring enzyme 1α (IRE1α). However, residue cancer cells that survive KRASi directly reactivated IRE1α through an ER stress–independent phosphorylation mechanism that reestablished proteostasis and sustained acquired resistance to KRAS inhibition. We identified four oncogenic signaling–regulated phosphorylation sites in IRE1α (Ser 525 , Ser 529 , Ser 549 , and Thr 973 ) that are distinct from IRE1α autophosphorylation sites but are required for enhanced protein stability. The phosphorylation of IRE1α at these sites prevents IRE1α binding with the SEL1L/HRD1 E3 ligase complex, thus impairing the ubiquitination-dependent degradation of IRE1α and stabilizing the protein. These sites are the convergence points of multiple resistance mechanisms in KRASi-resistant tumors. RTK-mediated reactivation of ERK and hyperactivation of AKT sustained the unconventional phosphorylation of IRE1α in the KRASi-resistant tumors, which consequently restored its protein stability and reestablished proteostasis. Genetic or pharmacological suppression of IRE1α collapsed the rewired proteostasis network and overcame resistance to KRAS–MAPK (mitogen-activated protein kinase) inhibitors. CONCLUSION This study reveals the direct cross-talk between oncogenic signaling and the protein quality control machinery and uncovers the mechanisms that account for the proteostasis rewiring in response to KRAS inhibition. Multiple resistance mechanisms converge on IRE1α through ER stress–independent phosphorylation to restore proteostasis and promote KRASi-resistant tumor growth. Targeting this key convergence point represents an effective therapeutic strategy to overcome KRASi resistance. Proteostasis reprogramming upon KRAS inhibition. Inhibition of oncogenic KRAS inactivates both cytosolic and ER protein quality control machinery by inhibiting HSF1 and IRE1α. Residual cells that survive KRASi directly restore IRE1α phosphorylation through receptor tyrosine kinase–mediated reactivation of ERK and hyperactivation of AKT, preventing IRE1α from SEL1L/HRD1–mediated ubiquitination and degradation. Multiple heterogeneous resistance pathways converge on IRE1α to reestablish proteostasis and promote resistance to KRASi.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abn4180
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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