The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis found that evolutionary terms were included in less than 1% of articles on the cancer treatment outcomes, and this has not changed in 30 years. Here, we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e., noncurable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations—a well-known evolutionary phenomenon termed “competitive release.” Alternative strategies, such as adaptive therapy, “ersatzdroges,” and double-bind treatments, shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long-term control. Cancer Res; 75(22); 1–6. ©2015 AACR.

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 1–13. ©2015 AACR.

Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a “resistance niche” adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed “osteocrines”) found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer. Cancer Res; 75(22); 1–11. ©2015 AACR.

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CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 1–6. ©2015 AACR.