PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer

Abstract

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in LKB1-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult-to-treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1 driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1 driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFN-γ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.

Exploring the Control of PARP1 Levels in High-Grade Serous Ovarian Cancer

“…Here, we demonstrated a critical role for IFN-γ/STAT1/STAT3 signaling in regulating PARP1 levels in HGSOC cells, in line with our recent results in cervical cancer [17], and with the emerging evidence on the functional interplay between the STATs signaling cascade and PARP1 [28][29][30][31].…”

“…Of note, it has become increasingly clear that PARP1 may act as a crucial regulator of STAT1/STAT3 transcriptional activity, although the results are not consistent. Specifically, it has been reported that when PARP1 is aberrantly activated in cancer cells, it blocks phosphorylation of STAT1 and STAT3 via the poly(ADP-ribosyl)ation, ultimately reducing their transcriptional activity [ 28 , 31 ]. In line with these findings, Martincuks and colleagues [ 30 ] showed that PARPi treatment promotes STAT3 activation in ovarian cancer cells, tumor-associated immune cells and fibroblasts, resulting in PARPi resistance and immunosuppression.…”

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

“…STK11 plays a crucial role in regulating cell damage repair, energy metabolism, and tumor immune responses[ 16 ]. The LKB1 protein comprises three major domains: The N-terminal non-catalytic domain (encoded by amino acids 1-49), the catalytic kinase domain (encoded by amino acids 49-309), and the C-terminal non-catalytic regulatory domain (encoded by amino acids 309-433)[ 1 , 17 ].…”

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…Simultaneous PARP1 inhibition and LKB1 loss can restore IFNγ signaling and transform the "cold" TME into a "hot" one, enhancing the effectiveness of immune therapies such as PD-1 blockade. 243 Therefore, under gene mutation in tumor cells, combining ICB therapy with the immune system is one of the future development directions of synthetic lethal therapy. These new approaches may bring intercell genetic interactions and non-cell-autonomous mechanisms into SL definition.…”

“…The mutant LKB1 led to DNA repair deficiency and excessive activation of PARP1, which reduces the STAT1 activity and inhibits the IFNγ pathway. Simultaneous PARP1 inhibition and LKB1 loss can restore IFNγ signaling and transform the “cold” TME into a “hot” one, enhancing the effectiveness of immune therapies such as PD‐1 blockade 243 . Therefore, under gene mutation in tumor cells, combining ICB therapy with the immune system is one of the future development directions of synthetic lethal therapy.…”