Cooperative targeting of tumor heterogeneity by combining an antibody-drug conjugate with precision medicines J Boshuizen1, L Koopman2, O Krijgsman1, A Shahrabi1, E Gresnigt2, M Ligtenberg1, D Vredevoogd1, K Kemper1, T Kuilman1, J Song1, N Pencheva2, M Geukes1, E Rozeman1, C Blank1, M Janmaat2, D Satijn2, E Breij2, P Parren2 and D Peeper1 1The Netherlands Cancer Institute; 2Genmab, the Netherlands
Despite considerable advances made for both targeted and immunotherapies, intratumor heterogeneity and therapy resistance remain key factors contributing to therapeutic failure. Regarding resistance, we recently uncovered the mechanism of “cancer drug addiction”, a clinically relevant phenomenon by which the survival of therapy-resistant tumor cells has become dependent on the very drugs that serve to eliminate them. Using a genome-wide CRISPR-Cas9 screen we discovered the ERK2-JUNB-FRA1 pathway to be essential for drug addiction, in melanoma and lung cancer1. Combining a drug holiday with chemotherapy induced massive DNA damage and synergistic death. These results may guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.
Tumor heterogeneity represents another major clinical problem. We showed previously that drug-resistant cells often express high levels of the RTK AXL2. AXL-high, but not AXL-low, melanoma cells are resistant to MAPK pathway inhibitors, rationalizing a differential therapeutic approach to combat tumor heterogeneity. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. AXL-107-MMAE, as a single agent, displays potent in vivo anti-tumor activity in PDX, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations within heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibit tumor growth. Furthermore, by acutely inducing AXL transcription, BRAF/MEK inhibitors potentiate the efficacy of AXL-107-MMAE. These findings provide proof-of-concept for the premise that rationalized combinatorial targeting of distinct populations within heterogeneous tumors may improve therapeutic impact3.
1Kong, X. et al.Nature 550, 2017 2Müller, J. et al.Nature Comm 5, 2014 3Boshuizen J. et al. (subm.)
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