Noncanonical roles of the immune system in eliciting oncogene addiction

Abstract

Summary Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression illustrating that cancers can be “oncogene addicted” [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases necessarily their surfeit of activation is paramaount to maintain a neoplastic state [11]. Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is mediated both through both tumor intrinsic cell-autonomous mechanisms including proliferative arrest, apoptosis, differentiation and cellular senescence [1,2,4,12] but also host-dependent mechanisms that interact with these tumor intrinsic programs [14,15]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16]. Hence, immune effectors are critically involved in tumor initiation and prevention [17-19] and progression [20], but also appear to be essential to tumor regression upon oncogene inactivation [21-23]. The understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both a robust tumor intrinsic as well as immunological effectively leading to sustained tumor regression.

Targeting FGFR Signaling in Cancer

“…Taking into account the currently available preclinical/clinical data, the most promising synergistic combination with minimally overlapping toxicities will associate FGFR inhibitors with (i) EGFR inhibitors (or inhibitors targeting other RTKs or downstream MAPK and PI3K/AKT signaling), (ii) endocrine therapy (ongoing trial NCT01202591 evaluating AZD4547 in combination with endocrine therapy in ER þ breast cancer), (iii) anti-VEGF (this is achieved by multikinase inhibitors), or (iv) immunotherapeutics (82).…”

An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

“…The MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors can induce potent T cell inhibition [134]. Imatinib has been shown experimentally to influence the immune response in a multitude of ways [34,58,135–139]. Similarly, targeted inactivation of oncogenes such as MYC and RAS could have profound effects on immune activation [34].…”

“…Imatinib has been shown experimentally to influence the immune response in a multitude of ways [34,58,135–139]. Similarly, targeted inactivation of oncogenes such as MYC and RAS could have profound effects on immune activation [34]. Consequently, it will be pivotal to consider that targeted oncogene inactivation can have positive and negative influences on the contribution of the immune system to the therapeutic response.…”

“…More recently, vemurafenib, which targets the BRAF V600E mutation, has been shown to have activity against melanoma [33]. Drugs that target oncoproteins such as ALK, JAK2, MDM2, and PI3 kinase are currently in clinical trials [34–43]. However, the most important driver oncoproteins, such as K-RAS and MYC, have remained undruggable, although strategies to target RAS [44] and MYC [45,46] have been recently described.…”

Oncogene withdrawal engages the immune system to induce sustained cancer regression

“…However, tumor regression following oncogene inactivation has been observed in response to targeted therapeutics in humans including molecules that target BCR-ABL or c-Kit, EGFR, ALK, BRAF V600E, PML-RARα, and HER2/neu for the treatment of leukemia, lung adenocarcinoma, non-small cell lung cancer, melanoma, and breast cancer [15-23]. Other drugs are in clinical investigation, including those that target JAK2, MDM2, and PI3 Kinase [24-31]; drugs that target RAS [32] and MYC [33,34] are in early development. It remains to be seen if these agents specifically take advantage of oncogene addiction.…”