A Convergence-Based Framework for Cancer Drug Resistance

Abstract

Despite advances in cancer biology and therapeutics, drug resistance remains problematic. Resistance is often multifactorial, heterogeneous, and prone to undersampling. Nonetheless, many individual mechanisms of targeted therapy resistance may coalesce into a smaller number of convergences, including pathway reactivation (downstream re-engagement of original effectors), pathway bypass (recruitment of a parallel pathway converging on the same downstream output), and pathway indifference (development of a cellular state independent of the initial therapeutic target). Similar convergences may also underpin immunotherapy resistance. Such parsimonious, convergence-based frameworks may help explain resistance across tumor types and therapeutic categories and may also suggest strategies to overcome it.

Keywords: cancer; drug resistance; heterogeneity; immunotherapy; precision medicine; targeted therapy.

Figure 1. The landscape of cancer therapeutics and resistance

Recent research has more fully elucidated the landscape of cancer’s oncogenic dependencies and immunologic vulnerabilities. Clinical interrogation of these features can guide treatment selection, leading to therapeutic response (top). However, drug resistance often limits cure or long-term control of advanced cancer. Resistance poses several challenges (bottom), in that it is multifactorial, heterogeneous, and therefore prone to undersampling. If resistance is to be overcome, new frameworks are needed to understand and address these challenges.

Figure 2. A convergence-based framework for cancer drug resistance

Mechanisms of resistance to targeted therapeutics converge into patterns on the basis of their relationship to the drug target and its downstream pathways. In a “pathway reactivation” convergence, resistance mechanisms re-engage the index effector pathway downstream of the drug target. “Pathway bypass” resistance uses alternate effectors to bypass the inhibited index effectors and re-engage the original downstream oncogenic output (e.g., transcriptional or translational state). “Pathway indifference,” in contrast, is characterized by an alternative cell state that is indifferent to inhibition of the drug target as well as its index effectors and oncogenic output. In each case, resistance mechanisms support an index or alternate oncogenic output that drives continued tumor progression.

Figure 3. Pathway reactivation as a resistance convergence

Pathway reactivation confers drug resistance by re-engaging index effectors downstream of the drug target, thereby maintaining the original oncogenic signaling output.

1. In BRAF-mutant melanoma, MAPK pathway inhibitors target BRAF and its index effectors in the MAPK pathway. Pathway reactivation mechanisms include target alterations (e.g., amplification or alternate splicing), which render BRAF insensitive to drug inhibition, as well as recruitment of upstream, parallel, and downstream effectors, which re-activate index effectors in a BRAF-independent fashion. These mechanisms reactivate the index MAPK pathway effectors downstream of BRAF, conferring resistance to BRAF inhibition.

2. In prostate cancer, oncogenic signaling through the androgen receptor (AR) is targeted by androgen-deprivation therapy and anti-androgen therapy. Resistance to AR-directed therapy can be mediated by pathway reactivation mechanisms including target alterations, which render AR itself resistant to drug inhibition, and recruitment of upstream effectors (non-gonadal androgens or alternate AR ligands), which reactivate drug-inhibited signaling through AR. In either case, the index oncogenic signaling downstream of AR is re-activated, conferring drug resistance.

Figure 4. Pathway bypass as a resistance convergence

Pathway bypass confers drug resistance by recruiting alternate effector pathways to sustain the index downstream oncogenic output (for example, transcriptional or translational state).

1. In BRAF-mutant melanoma, pathway bypass mechanisms reactivate the core MITF transcriptional output in a manner that is independent of upstream MAPK input. For example, a GPCR-cAMP-CREB signaling axis can substitute for MAPK signaling to sustain an MITF-driven transcriptional program. Likewise, MITF amplification can render MITF itself independent of MAPK signaling.

2. In prostate cancer, signaling through the glucocorticoid receptor (GR) drives a transcriptional program similar to that of the index AR signaling pathway, rendering cells resistant to inhibition of the AR axis.

Figure 5. Pathway indifference as a resistance convergence

Pathway indifference confers drug resistance via an alternate cellular state that is independent of the index drug-inhibited pathway and its original oncogenic effectors.

1. In BRAF-mutant melanoma, the index drug-sensitive transcriptional state is characterized by MAPK-dependent activity of the MITF transcription factor. Resistance to MAPK pathway inhibition can be achieved by transition to an NF-κB-driven, low-MITF transcriptional state that does not require MAPK input for its maintenance.

2. In prostate cancer, alternative AR-independent cellular states are characterized by Wnt5A-driven and neuroendocrine-like transcriptional programs and are indifferent to inhibition of the AR signaling axis.

Figure 6. Convergences in resistance to immunotherapy

1. Anti-tumor immunity requires a multi-step cycle to achieve immune cell clearance of tumor cells.

2. Many immunotherapy resistance mechanisms converge on modulation of neoantigen expression, processing, or presentation, thus restoring the index state of escape from anti-tumor immunity.

3. Alternatively, induction of T cell dysfunction can bypass anti-tumor immunity, either directly (e.g., through alternative checkpoint ligands) or indirectly (e.g., through T regulatory cells or the tumor microenvironment).

4. Finally, certain oncogenes or malignant cell states may confer an “immune indifferent” resistance state.