Beyond Oncogenes: Selectively Targeting Whole-Tumor Cell Growth Regulation

Enormous progress has been made in developing targeted, anti-cancer drugs such as small-molecules, monoclonal antibodies and antibody-conjugated drugs.^1,2 Newer immunotherapies and cell-based therapies via immunological responses against cancer cells have further revolutionized the treatment.³ However, cancer remains largely incurable. In anticancer drug development, targeting oncogenes is a logic and common approach but faces challenges including identification of “driver” oncogenes and drug resistance due to additional mutations or other factors including epigenetic changes, phenotypic adaptation, influences from the tumor microenvironment, and reconfiguration of intercellular signal networks.^4–7 A natural anti-cancer system that selectively inhibits tumor cells by interfering with their growth-regulatory machinery may provide insightful clues for possible therapeutic approaches.

In humans, many de novo cancerous or transformed cells are eliminated before fully developing into cancer. One reason for this is a cell cycle-based anticancer surveillance system that monitors cancer cell development, alongside immunosurveillance.^8,9 In this system, selective changes in the tumor cell growth-regulation, including activation of the cell cycle regulator p107 in response to interferon-beta and -alpha (IFNβ- and IFN-α) expression, impose a cell cycle checkpoint to suppress tumor cell growth and promote senescence, diminishing tumorigenicity.^8,10 This system bypasses specific oncogenes and selectively inhibits tumor cells at the cellular level. Normally growing cells are largely unaffected because they are tightly controlled by the normal cell cycle-regulatory machinery, of which a key component is RB1 (or pRB).^8,11 Additionally, IFN-β induces apoptosis of tumor cells when overexpressed,¹² further enhancing the elimination of cancer cells. This network of actions reflects an effective natural anticancer mechanism at the cellular level.

The cell cycle-based surveillance system is an evolutionary adaptation aligned with the complex and heterogeneous nature of cancer in higher-order organisms. Figure 1 schematically illustrates the correlation between evolutionary development, cancer complexity/heterogeneity, and refinement of the surveillance system using four representative species, from Caenorhabditis (C). elegans to Homo sapiens. C. elegans does not develop cancer; it possesses only the RB1 ortholog LIN35 and lacks IFNs and p107.^13,14 Drosophila can develop simple cancers and serves as a valuable model for studying oncogene-tumor suppressor gene interactions, but it possesses only the RB1 homologs Rbf1 and Rbf2, without p107.¹⁵ Although drosophila has the JAK/STAT pathway that can help restrict viral infection, it lacks IFNs.¹⁶ Mice develop more sophisticated cancers, yet their cell cycle-based anticancer surveillance is less robust than in humans. Murine IFN-β does not elicit as strong a cell cycle effect on mouse cancer cells as human IFN does on human cancer cells.¹⁷ In humans, cell cycle-based anticancer surveillance has evolved into a coordinated regulatory mechanism between tumor cells and normal cells. This system selectively suppresses cancer cells, regardless of their heterogeneity and driver oncogenes.^8,11 It in turn suggests that a therapeutic approach, following this mechanism, can potentially override tumor cell heterogeneity and be applied to different types of cancer.

Figure 1 Schematic diagram illustrates the correlation between evolutionary development, cancer complexity/heterogeneity, and refinement of the surveillance system using four representative species, from Caenorhabditis (C.) elegans to Homo sapiens.

The cancer cell surveillance and removal speak of the importance of targeting cancer at the level of whole-cell growth regulation rather than simply targeting oncogenes. Oncogenic activation or tumor suppressor loss-of-function initiates carcinogenesis, but once established, cancer cells acquire other irreversible alterations in their growth-regulatory machinery, including additional mutations and/or epigenetic changes (Figure 2). Consequently, targeting oncogenes that initiate tumorigenesis or reintroducing a tumor suppressor alone will not reverse oncogenesis. This limitation helps explain why many therapies aimed at individual oncogenes are clinically efficacious, leading to improved survival and quality of life, but still face gaps in durable benefits (ie, long-term cancer-free remission). Combination regimens that target known oncogenes yield notable responses, yet overall efficacy remains suboptimal. Consequently, targeted therapies that selectively address the entire cancer cell are essential, since cancerous cells harbor irreversible growth-regulatory defects that extend beyond the initiating oncogenic event. Therapies that selectively interfere with growth regulation of cancer cells would work differently from cell-based immune therapies, which target cancer cells via immune responses.

Figure 2 Graph shows that once established, cancer cells have acquired irreversible alterations in their growth-regulatory machinery that extend beyond the initiating oncogenic event.

Targeted therapy at the cellular level has advanced markedly in the management of myeloproliferative neoplasms. Polycythemia vera, a type of myeloproliferative neoplasm characterized by erythrocytosis, classically harbors the constitutively active driver mutation JAK2^V617F. Here, ropeginterferon alfa-2b, a mono-PEGylated proline-interferon-α with an exposure-related response profile, represents a therapy targeting the neoplasm at the whole-cellular level.^18,19 It exerts an anti-neoplastic effect by IFN receptor-mediated activation of JAK1/Tyk2 kinases, bypassing the mutated JAK2.²⁰ Ropeginterferon alfa-2b treatment achieves high rates of hematologic and deep molecular responses, provides a survival advantage in patients with polycythemia vera, and has shown clinical benefits in other myeloproliferative neoplasms.^21–24 The clinical results thus exemplify the promise of targeting whole-cell growth in oncology. Building on this backbone, combining such agents with complementary targeted therapies may yield even greater therapeutic gains. Consistently, combining epigenetic therapies with other treatments to overcome therapeutic resistance shows great potential in cancer therapy.^25,26

In summary, targeting whole-cell growth regulation, thereby extending beyond focusing on single-oncogene inhibition, adds an important dimension to cancer treatment, either as monotherapy or potentially in combination with other mechanistic approaches. The clinical efficacy of ropeginterferon alfa-2b in myeloproliferative neoplasms provides a concrete illustration of this paradigm. A potential limitation of this strategy is that it remains a challenge to precisely distinguish and selectively interfere with tumor cell growth-regulatory networks in various cancer types without affecting normal cells.