Paper: Marin-Bejar O., et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell. 2021 Aug 9;39(8):1135-1149.e8. doi: 10.1016/j.ccell.2021.05.015.
Background:
In cancer, therapy resistance is thought to mainly occur through the acquisition of genetic alterations, but increasing evidence indicates that drug resistance can be acquired through non-genetic mechanisms as well. In melanoma, the genetic vs nongenetic mechanisms of resistance are unclear. This study investigated these two trajectories in PDX models that had been subjected to combination therapy targeting the MAPK pathway. The team assessed whether there were molecular features of melanoma minimal residual disease (MRD) that determine which of the two resistance mechanisms occurs.
Question:
Can single-cell analysis reveal mechanisms of resistance in melanoma?
Methods:
The authors investigated both genetic and nongenetic mechanisms of resistance in BRAF-mutant melanoma after treatment with the combination therapy: dabrafenib + trametinib (both of which inhibit the MAPK signaling pathway). The group used BRAF-mutant PDX models established from treatment-naive patients.
To understand the genetic mechanisms of resistance, the team performed bulk sequencing as well as single-nuclei sequencing using Mission Bio’s Tapestri Platform and single-nuclei protocol. This type of sequencing enables solid tissue (fresh frozen) to be analyzed. For any genetic mechanisms of resistance, the authors wanted to know whether resistant cells were preexisting prior to treatment (primary resistance) or arose during treatment (secondary resistance).
The authors also investigated nongenetic mechanisms of resistance in melanoma by assessing the transcriptional states in cells with drug tolerant persister (DTP) phenotypes and evaluating if any genetic mutations were present.
Main Results:
This study investigated the emergence of genetic vs non-genetic resistance to MAPK therapeutics in melanoma. Their results illustrated that both mechanisms occur. For genetic mechanisms of resistance, the authors found the presence of an acquired NRAS resistance-conferring mutation in one sample. Tapestri analysis confirmed that this mutation was acquired during treatment (i.e., it was not present in a pre-existing subclone prior to treatment).
For nongenetic mechanisms of resistance, the authors found a transient neural crest stem-like cell (NCSC) population emerged post-treatment. They found that nongenetic resistance only developed following the emergence of these NCSCs. These cells had activated FAK signaling, and targeting these cells using an FAK inhibitor prevented the evolution of nongenetic drug resistance. The team concluded that whether resistance in melanoma takes a genetic or nongenetic trajectory is based on the cellular composition of MRD. (Note: Tapestri was not used in the nongenetic analyses).
Conclusion:
This paper illustrates that multiple trajectories of resistance to anti-cancer therapies— whether genetic or nongenetic— can exist. The use of single-cell nuclei sequencing via Tapestri can help establish which of these two trajectories is occurring in melanoma MRD, as well as in other solid tumors.
These findings have significant implications for the potential treatment of therapy-resistant melanoma, as they suggest that success may depend on MRD composition. As melanoma MRD composition varies across individuals, personalized MRD-targeted therapies may be the best way to treat resistant disease.
The study highlights the value of single-cell analysis to dissect how cancer evolves resistance to therapeutic agents and can aid in personalized treatment strategies that overcome such mechanisms.
Check out the paper here!
