We showed that UBQLN4 overexpression significantly co-clusters with KRAS mutations in NSCLC, represses homologous recombination (HR) and is associated with poor survival in NSCLC.
We further showed that HR defects are associated with PARP inhibitor (PARPi) sensitivity. Moreover, HR defects lead to increased mutation frequency. Thus, we will characterize the efficacy of PARPi and immune checkpoint blockade, to provide a rationale for the clinical validation of these experiments in NSCLC patients harboring oncogenic KRAS and UBQLN4 overexpression.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Particularly in lung adenocarcinoma (LuAc, the largest NSCLC subset), the identification of actionable aberrations in kinase genes led to improved patient survival. However, in ~32% of LuAcs, mutated KRAS has been identified, for which no direct targeting approach exists. Further analysis determined loss-of-function alterations in central components of the DNA damage response (DDR), such as in TP53 and ATM, suggesting an impaired DDR may be selected in KRAS-mutant LuAc. Specifically, a defect in homologous recombination (HR) has been associated with a marked sensitivity against PARP1 inhibitors.
We recently identified UBQLN4 as a master regulator, which represses HR by removing MRE11 from damaged chromatin. Importantly, UBQLN4 overexpression significantly co-clusters with oncogenic KRAS mutations in LuAc. Moreover, UBQLN4 overexpression is associated with reduced overall survival in LuAc.
With the generation of conditional Ubqln4 knockin mice in combination with autochthonous mouse models of Kras-driven LuAc, we will elucidate the preclinical efficacy of PARP1 inhibitiors (PARPi) in these tumors. We will further flesh out the mechanism of how UBQLN4 is overexpressed in KRAS-mutant LuAc. It is conceivable that HR defects are associated with increased tumor mutational burden, which has been shown to be predictive of favorable response to immune checkpoint inhibitors (ICI) in LuAc. Thus, we will also assess the potential of anti-PD1 treatment in HRR-defective KRAS-mutant LuAcs.
Validate PARP1 inhibitor sensitivity in UBQLN4-overexpressing Kras-driven lung adenocarcinoma in vivo.
Identify the mechanism of UBQLN4 overexpression in Kras-driven lung adenocarcinoma and additional druggable targets in HRR defective settings.
Elucidate the influence of UBQLN4 expression on immunogenicity and immunotherapy with anti-PD-1 antibodies in Kras-driven lung adenocarcinoma.
Genome instability is a hallmark of both, certain human syndromes (so-called genome instability syndromes) and cancer. We recently identified a deleterious UBQLN4 mutation in two consanguineous families with an autosomal recessive syndrome reminiscent of known genome instability disorders. Using cells from the affected individuals, as well as genetically engineered cells, we showed that UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HR).
We demonstrated that loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HR and favors the use of error-prone and mutagenic non-homologous end joining.
Moreover, we found that UBQLN4 is overexpressed in aggressive tumors. In line with an HR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
Clinic for Hematology - Uniklinik Essen
Principal Investigator - A 10show more…
Clinic for Hematology - Uniklinik Essen
present adress: Universitätsklinikum Essen (AöR) Hufelandstraße 55
Curriculum Vitae (CV)
Department I of Internal Medicine
Co-Principial Investigator - A 10show more…