Novel targeted strategies to overcome resistance in small-cell lung cancer: focus on PARP inhibitors and rovalpituzumab tesirine

ABSTRACT

Introduction: Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumour, and its outcome is strongly conditioned by the rapid onset of resistance to conventional chemotherapeutics. First-line treatment with a combination of platinum agents and topoisomerase inhibitors has been the standard of care for over 30 years, with disappointing clinical outcome caused by early-acquired chemoresistance. In this disheartening scenario, novel treatment strategies are being implemented in order to either revert or bypass resistance mechanisms.

Areas covered: The general mechanism of action of the standard frontline treatment regimens for SCLC, as well as the known resistance mechanisms to these drugs, is reviewed. Moreover, we focus on the current preclinical and clinical evidence on the potential role of PARP inhibitors and rovalpituzumab tesirine (Rova-T) to tackle chemoresistance in SCLC.

Expert opinion: Preliminary evidence supports PARP inhibitors and Rova-T as two promising approaches to either revert or bypass chemoresistance in SCLC, respectively. The identification of potential predictive biomarkers of response to these innovative treatments (SLFN11 and DLL3) has shortened the gap between SCLC and personalized targeted therapy. Further large-scale clinical studies are urgently needed for a better designation of PARP inhibitors and Rova-T in the therapeutic algorithm of SCLC patients.

KEYWORDS:

• Small-cell lung cancer (SCLC)
• chemoresistance
• PARP inhibitors
• Notch pathway
• DLL3
• rovalpituzumab tesirine
• targeted therapy

Article highlights

• Small-cell lung cancer (SCLC) is an aggressive disease characterized by a rapid onset of resistance to chemotherapeutics and a 5-year overall survival rate lower than 7%;

• Resistance mechanisms to conventional cytotoxic drugs (platinum analogs and topoisomerase inhibitors) mainly rely on reduced drug accumulation, increased drug inactivation, increased DNA damage repair, aberrations in drug metabolism and inhibition of apoptosis;

• PARP inhibitors and rovalpituzumab tesirine have shown promising preclinical and clinical activity in either reverting or bypassing chemoresistance, respectively;

• Large-scale randomized trials and a better characterization of biomarkers that can predict response to these novel treatments are largely awaited.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Italian Association for Cancer Research (AIRC grant IG2017-20074 to M Tiseo, and Start-Up grant to E Giovannetti).