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Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer

Marcello Stanzione1, Jun Zhong1, Edmond Wong1

  • 1Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Science Advances
|May 13, 2022
PubMed

Insights

Researchers studied acquired resistance to olaparib plus temozolomide (OT) in small cell lung cancer (SCLC). They found that up-regulation of translesion DNA synthesis (TLS) confers resistance, but TLS inhibitors can restore sensitivity to OT.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acquired resistance to DNA-damaging therapy poses a significant challenge in treating small cell lung cancer (SCLC).
  • Studying resistance mechanisms is difficult due to the infrequent performance of tumor rebiopsies in SCLC patients.
  • Olaparib plus temozolomide (OT) is a promising experimental therapy for relapsed SCLC.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to olaparib plus temozolomide (OT) in small cell lung cancer (SCLC).
  • To utilize patient-derived xenograft (PDX) models to dissect acquired resistance to OT therapy.
  • To identify potential therapeutic strategies to overcome OT resistance in SCLC.

Main Methods:

  • Establishment and analysis of serial patient-derived xenograft (PDX) models of SCLC, before and after therapy.
  • Assessment of alterations in cell cycle kinetics and DNA replication in resistant models.
  • Evaluation of the role of translesion DNA synthesis (TLS) in mediating resistance to OT.
  • Testing the efficacy of TLS inhibitors in combination with OT in vitro and in vivo.

Main Results:

  • Serial PDX models revealed both inter- and intratumoral heterogeneity in resistance mechanisms.
  • Up-regulation of translesion DNA synthesis (TLS) was identified as a key mechanism enabling tolerance of OT-induced DNA damage during replication.
  • TLS inhibitors restored sensitivity to OT in resistant SCLC models, demonstrating synergistic effects.
  • Similar synergistic effects were observed in additional SCLC cell lines.

Conclusions:

  • This study describes the first identified mechanism of acquired resistance to DNA-damaging therapy in SCLC.
  • Up-regulation of translesion DNA synthesis (TLS) is a critical mechanism of acquired resistance to olaparib plus temozolomide (OT) in SCLC.
  • The serial PDX model approach is valuable for investigating and overcoming therapeutic resistance in SCLC, with TLS inhibitors showing promise for combination therapy.

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