TY - JOUR
T1 - Resistance to chemotherapy
T2 - Patient variability and cellular heterogeneity
AU - Kessler, David A.
AU - Austin, Robert H.
AU - Levine, Herbert
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - The issue of resistance to targeted drug therapy is of pressing concern, as it constitutes a major barrier to progress in managing cancer. One important aspect is the role of stochasticity in determining the nature of the patient response. We examine two particular experiments. The first measured the maximal response of melanoma to targeted therapy before the resistance causes the tumor to progress. We analyze the data in the context of a Delbruck-Luria type scheme, wherein the continued growth of preexistent resistant cells are responsible for progression. We show that, aside from a finite fraction of resistant cell-free patients, the maximal response in such a scenario would be quite uniform. To achieve the measured variability, one is necessarily led to assume a wide variation from patient to patient of the sensitive cells' response to the therapy. The second experiment is an in vitro system of multiple myeloma cells. When subject to a spatial gradient of a chemotherapeutic agent, the cells in the middle of the system acquire resistance on a rapid (two-week) timescale. This finding points to the potential important role of cell-to-cell differences, due to differing local environments, in addition to the patient-to-patient differences encountered in the first part.
AB - The issue of resistance to targeted drug therapy is of pressing concern, as it constitutes a major barrier to progress in managing cancer. One important aspect is the role of stochasticity in determining the nature of the patient response. We examine two particular experiments. The first measured the maximal response of melanoma to targeted therapy before the resistance causes the tumor to progress. We analyze the data in the context of a Delbruck-Luria type scheme, wherein the continued growth of preexistent resistant cells are responsible for progression. We show that, aside from a finite fraction of resistant cell-free patients, the maximal response in such a scenario would be quite uniform. To achieve the measured variability, one is necessarily led to assume a wide variation from patient to patient of the sensitive cells' response to the therapy. The second experiment is an in vitro system of multiple myeloma cells. When subject to a spatial gradient of a chemotherapeutic agent, the cells in the middle of the system acquire resistance on a rapid (two-week) timescale. This finding points to the potential important role of cell-to-cell differences, due to differing local environments, in addition to the patient-to-patient differences encountered in the first part.
UR - http://www.scopus.com/inward/record.url?scp=84907055561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907055561&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-14-0118
DO - 10.1158/0008-5472.CAN-14-0118
M3 - Article
C2 - 25183790
AN - SCOPUS:84907055561
SN - 0008-5472
VL - 74
SP - 4663
EP - 4670
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -