New Paper published: Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma

Very excited to announce that our latest work, a joint collaboration led by fantastic Dr David Croucher and his lab at the Garvan Institute has just been published in the leading international journal eLife1. You can download and access the full article for free here [Link].

Key Points we made in the paper are:

  1. Most previous preclinical models have used unrealistic extreme exposure methods.
  2. Using a pulse model that closely mimics the how patients received platinum in the clinic, results in very different response compared to previous extreme exposure models.
  3. Using a systems biology approach we modelled the kinetic changes that occur across the major signalling pathways in multiple lung cancer cell lines after a pulsed exposure to platinum
  4. This identified a number of key factors that determine how cells respond.
  5. We found that P70S6K-mediated signalling was key to promoting platinum resistance in cells that contained wild-type or lacked p53.
  6. We validated this using a chemical inhibitor and with RNAi, finding that targeting P70S6K could sensitise cells to platinum both in vitro and in mice models.

Why is this important: Well Platinum chemotherapy is a frontline chemotherapy for many cancer types including small-cell lung cancer, ovarian, head and neck, bladder and cervical cancers ovarian cancer and it is curative in >90% of testicular cancers.

But in lung adenocarcinoma (LUAD), which is the most common form of lung cancer and the leading cause of cancer-related death in Australia, response rates to platinum are <30%. A major reason for this is that LUAD are ‘naturally’ (innately) more resistant to platinum. This has led to a large amount of research looking into why LUAD cells are more resistant, and to date over 150 different potential mechanisms have been identified. Unfortunately, the vast majority of these have failed to translate clinically into better patient response and survival2.

We hypothesised that this might be in part to the way previous research had used very high dose and continuous multi-day exposure methods when looking for mechanisms of resistance. This is in notable contrast to how it’s delivered to patients, where it is given as a single bolus dose. This reaches a peak concentration of about 5µg/ml in patients plasma, which is then rapidly cleared by the kidneys within 2-4 hours.

Although still in the early days, we hope that these results lead improved patient outcomes and better response to platinum chemotherapy.
We also hope that this helps promote the use of more clinically relevant lab models that can improve and reduce the number of off-target hits and faster translation of results for patients.

References

1 Hastings, J., Rajal, A., Latham, S., Han, J., McCloy, R., O’Donnell, Y., Phimmachanh, M., Murphy, A., Nagrial, A., Daneshvar, D., Chin, V., Watkins, D., Burgess, A., Croucher, D. (2020). Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma eLife 9 https://dx.doi.org/10.7554/elife.53367
2 Gonzalez-Rajal, A., Hastings, J., Watkins, D., Croucher, D., Burgess, A. (2020). Breathing New Life into the Mechanisms of Platinum Resistance in Lung Adenocarcinoma Frontiers in Cell and Developmental Biology 8(), 305. https://dx.doi.org/10.3389/fcell.2020.00305

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