Virtual Library

Start Your Search

Kristin Gurtner



Author of

  • +

    PD01 - Poster Discussion Session (ID 4)

    • Event: NACLC 2019
    • Type: Poster Discussion Session
    • Track:
    • Presentations: 1
    • +

      PD01.15 - Targeting the Chemoradiation Resistance of Lung Cancers With KRAS/TP53 Co-mutations (ID 85)

      15:45 - 16:45  |  Author(s): Kristin Gurtner

      • Abstract

      Background:
      Recent clinical data have linked KRAS/TP53 (KP) co-mutations (mut) to resistance to radiotherapy (RT), but supporting laboratory evidence is sparse. In addition, the ability of different radiation doses, with/without EGFR-directed treatment, to achieve local tumor control as a function of KRAS status is unknown.


      Method:
      Clonogenic radiation survival of a panel of 17 non-small cell lung carcinoma (NSCLC) cell lines was assessed. The radiosensitivity of isogenic TP53mut NCI-H1703 models, KRASmut or wild-type (wt), was measured in vitro and in heterotopic xenografts in nude mice, with/without concurrent drug treatment. In vivo experiments employed 30 RT fractions over 6 weeks. The dose that controlled 50% of tumors (TCD50) was calculated.


      Results:
      KRASmut cell lines demonstrated higher in vitro survival compared to wt lines (average 1.3-fold across all dose points). A similar observation was made when cell lines were grown under anchorage-independent growth conditions, shown to support the oncogenic phenotype of KRASmut cells. KP+ cell lines tended to express the highest relative level of radioresistance compared to the other genotypes. The TCD50 for KRASwt/TP53mut NCI-H1703 xenografts was 43.1 Gy whereas KRASmut/TP53mut tumors needed a 1.9-fold higher dose of 81.4 Gy (Fig. 1). Interestingly, erlotinib radiosensitized KRASmut but not KRASwt cells in 2 isogenic models. The radiosensitizing effects of erlotinib and other small molecule inhibitors targeting the EGFR pathway in KRASmut cells were preserved when cisplatin was administered concurrently. In vivo radiosensitization by erlotinib was seen as well, i.e., TCD50=58.8 Gy for erlotinib/RT in KRASmut xenografts, corresponding to a ~1.4-fold dose enhancement, but wt xenografts were not radiosensitized.
      Fig. 1. Co-clinical trial of radiation dose escalation in a xenograft model

      Conclusion:
      We nominate KP status as an actionable predictive biomarker to guide the administration of RT +/-chemotherapy in localized NSCLC. For these tumors, radiation dose escalation and, unexpectedly, targeting the EGFR pathway constitute potential strategies to overcome the chemoradiation resistance associated with this genotype. Support: NCI U01CA220714, ACS 123420RSG-12-224-01-DMC