The basis for resistance to
VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to
VEGF-A inhibition by a loss-of-function analysis using plasmid-based
shRNA.
Tumor xenografts that initially responded to
VEGF-A inhibition underwent an adaptation in vivo, leading to acquired resistance.
VEGF-A blockade in
tumors was associated with HIF1α expression and an increase in CD144(+) vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133(+) and
CD271(+)
melanoma stem-like cells (MSLC) accumulated in the perivascular niche.
Tumor xenografts of
melanoma cell populations that were intrinsically resistant to
VEGF-A blockade did not exhibit any of these features, compared with nontarget control counterparts. Thus,
melanomas that are initially sensitive to
VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through an HIF1α-dependent process. Conversely,
melanomas that are intrinsically resistant to
VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-
VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like
cancer cells, with implications for how to design combination
therapies that can improve outcomes in patients.