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Page 2 of 11 Tessari et al. J Cancer Metastasis Treat 2020;6:18 I http://dx.doi.org/10.20517/2394-4722.2020.32

focused on the role of RANBP9 in the response to DNA damage, particularly in the context of NSCLC. This review
concludes with future directions and speculative remarks which will need to be addressed in the coming years.

Keywords: RANBP9, RANBP10, Scorpins, DNA damage, DNA repair, DNA damage response, CTLH complex,
cisplatin, non-small cell lung cancer, PARP, BRCAness-like phenotype

OUTLINE
As an introduction, we will briefly mention the state-of-the-art strategies in the treatment of NSCLC, as
well as the main molecular features of RANBP9. Moving on, we will then succinctly discuss RANBP9
in cancer generally, before focusing on the role of RANBP9 specifically in the cellular response to DNA
damage of NCSLC cells.

INTRODUCTION
Non-small cell lung cancer
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the developed
world [1-3] . The standard of care for NSCLC during the last decades has been the use of combination
[4,5]
chemotherapy, including that of platinum-based drugs . Significant progress has been made in the
treatment of this devastating disease through the development of targeted therapies for tumors expressing
oncogenic driver alterations (examples include that of EGFR mutations and ALK rearrangements) [6-8] .
Nevertheless, the vast majority of NSCLC patients treated with targeted therapy commonly exhibit de novo
[7]
or acquired resistance .

Treatment with immune checkpoint inhibitors (ICIs) has been transformational in the management of
NSLCLC. These drugs have now set new standards to the point that ICIs evolved to become first-line
treatment [9-14] . However, for unknown reasons, an estimated half of the NSCLC patients are refractory to
this new modality and the majority become resistant after an initial response [15-18] .

From a clinical and basic science perspective, the relationship between tumor mutational burden and
[19]
response to ICIs is of great interest . It is known that tumors with high mutational burden tend to be
[20]
immunologically “hot”, displaying favorable responses to treatment . Therefore, the specific mechanisms
of the DNA damage response (DDR) causing the tumor to be more vulnerable to ICIs represent an active
area of research and investigation. Clinical trials testing whether the use of low doses of DNA damaging
agents may sensitize advanced NSCLC to targeted or immuno-therapies are ongoing [21-23] . Therapeutic
regimens include both platinum-based drugs and ICIs for advanced NSCLC, which have shown superior
results compared to the use of chemotherapy alone [21,24] .Upon first line or after failure of targeted- and/
or immune therapies, the vast majority of patients will undergo treatment with platinum-based cytotoxic
drugs. Hence, seeking out new modalities of DDR which can be used as biomarkers to better stratify
patients, or as new therapeutic targets represents a valuable clinical and experimental goal [25,26] .

Molecular features of RANBP9
The RAN Binding Protein 9 (RANBP9; a.k.a. RANBPM) is a scaffold protein consisting of 5 regions/
[27]
domains known to mediate protein-protein interactions [Figure 1A]. RANBP9 is highly conserved
throughout evolution, suggesting that they maintain critical biological functions [28,29] . The perturbation
of its expression has shown that RANBP9 modulates the stability, turnover, and consequently signaling,
of a number of proteins involved in crucial biological processes/signaling pathways . It is thought that
[30]
RANBP9 exhibits these effects as a component of a ubiquitously expressed multi-subunit structure known