Oncogenes vs. Tumor Suppressors — Explain oncogenes vs tumor suppressors conceptually - Cell Biology

SECTION 1

Historical Context & Motivation

For most of the twentieth century, cancer was considered a disease of mysterious origin — attributed variously to viruses, chemicals, or simple misfortune. The conceptual revolution that transformed oncology into a molecular science hinged on a single realization: cancer arises from mutations in the cell's own genes. Two categories of genes emerged as the central protagonists and antagonists of this story — oncogenes, which promote cell growth when mutated, and tumor suppressor genes, which restrain it. Understanding how these two gene classes function, and how their disruption cooperates to produce malignancy, is foundational to modern cancer biology, targeted therapeutics, and precision medicine.

1911 • Rous Sarcoma Virus

Peyton Rous demonstrates that a filterable agent — later identified as a retrovirus — can transmit solid tumors in chickens, providing the first evidence that specific genetic elements can cause cancer.

1970s • Discovery of v-src and c-src

Harold Varmus and J. Michael Bishop show that the oncogene carried by the Rous sarcoma virus (v-src) originated from a normal cellular gene (c-src), establishing the proto-oncogene concept. They received the 1989 Nobel Prize for this insight.

1971 • Knudson's Two-Hit Hypothesis

Alfred Knudson analyzes retinoblastoma incidence in children and proposes that both alleles of a protective gene (later identified as RB1) must be inactivated for tumor formation — the foundational model for tumor suppressor genes.

1986 • Cloning of RB1

The retinoblastoma gene is cloned, becoming the first confirmed tumor suppressor. Its protein product, pRb, is shown to regulate the G₁/S cell-cycle checkpoint.

1989–Present • TP53 and the Genomic Era

TP53 is reclassified from a suspected oncogene to the most frequently mutated tumor suppressor in human cancers. Large-scale sequencing projects (TCGA, ICGC) catalogue hundreds of oncogenes and tumor suppressors, enabling targeted therapy development.

These discoveries raised a central question that organizes modern cancer genetics: how do gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressors cooperate to drive a normal cell through the multistep path toward malignancy? The remainder of this lesson unpacks that question systematically.

SECTION 2

Core Principles & Definitions

At the heart of this topic lies a simple but powerful dichotomy. Normal cells maintain a precise balance between proliferative signals and growth-restraining checkpoints. Cancer emerges when this balance is disrupted — typically through the simultaneous activation of growth-promoting pathways and the disabling of protective mechanisms. The genes underlying these two sides of the balance sheet are classified as proto-oncogenes (whose mutated forms are oncogenes) and tumor suppressor genes. Grasping the fundamental principles governing each class is essential before examining their molecular mechanisms in greater detail.

Proto-oncogenes → Oncogenes

Proto-oncogenes are normal genes encoding proteins that promote cell growth, division, or survival (e.g., growth factors, receptor tyrosine kinases, transcription factors). A gain-of-function mutation converts a proto-oncogene into an oncogene, producing a constitutively active or overexpressed protein. Only one mutant allele is typically sufficient — oncogenes act in a dominant fashion.

Tumor Suppressors

Tumor suppressor genes encode proteins that inhibit proliferation, promote apoptosis, or maintain genomic integrity (e.g., pRb, p53, BRCA1). Cancer requires loss-of-function in both alleles — they behave in a recessive manner at the cellular level (Knudson's two-hit model).

The Accelerator–Brake Analogy

An oncogene is like a stuck accelerator pedal — a single jammed pedal drives the car forward uncontrollably. A defective tumor suppressor is like failed brakes — you need both brake lines to fail before you truly lose stopping power. Cancer is a car with a stuck accelerator AND no brakes.

Multistep Carcinogenesis

Rarely does a single mutation suffice. Human cancers typically accumulate 4–7 driver mutations across multiple oncogenes and tumor suppressors over years or decades. This sequential accumulation model, formalized by Bert Vogelstein for colorectal cancer, explains why cancer incidence rises steeply with age.

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KEY TAKEAWAY

Think of cell division as a car traveling down a road. Proto-oncogenes are the engine and accelerator — they make the car go. Tumor suppressors are the brakes, speed governors, and airbags — they keep the car under control. An oncogenic mutation is a stuck accelerator (one defective pedal is enough to cause trouble), while a tumor suppressor mutation is a cut brake line (you need both lines cut, because one functioning line can still stop the car). Cancer develops when multiple systems fail simultaneously — the car accelerates without restraint, crashes through barriers, and cannot be stopped.

SECTION 3

Visual Explanation — The Balance of Growth Control

The diagram contrasts the normal regulatory state (center, amber border) with the cancer state (bottom, red border). On the left, proto-oncogenes are shown transitioning to constitutively active oncogenes via a single gain-of-function mutation. On the right, tumor suppressors require two hits to lose both functional alleles. Cancer results when both systems are compromised simultaneously.

The diagram above captures the essential conceptual framework. In a normal cell, growth-promoting signals from proto-oncogene products (left panel, violet) are precisely counterbalanced by tumor suppressor proteins (right panel, pink) that enforce checkpoints, trigger DNA repair, or initiate apoptosis when damage is detected. The balanced state (center, amber) represents controlled, regulated proliferation — cells divide only when appropriate extracellular signals are received and intracellular conditions are favorable.

The critical distinction in mutation genetics is this: oncogenes behave as dominant gain-of-function alleles because a single hyperactive copy is sufficient to overwhelm normal signaling — like a single stuck accelerator. Tumor suppressors behave as recessive loss-of-function alleles at the cellular level because one functional copy can still produce enough protein to maintain checkpoint control. Only when both alleles are eliminated (the 'two-hit' model) does the brake system fail entirely. This asymmetry has profound implications for cancer genetics, inheritance patterns, and therapeutic targeting.

SECTION 4

Molecular Mechanisms of Activation & Inactivation

Mechanisms of Oncogene Activation

Proto-oncogenes can be converted to oncogenes through several distinct molecular mechanisms. The first and perhaps most intuitive is point mutation, exemplified by the RAS family of GTPases. A single amino acid substitution at codon 12, 13, or 61 of KRAS locks the protein in its GTP-bound active conformation, constitutively signaling through the MAPK and PI3K/Akt pathways. This mutation is found in approximately 25% of all human tumors, including 90% of pancreatic adenocarcinomas.

A second mechanism is gene amplification, in which extra copies of a proto-oncogene are produced through chromosomal replication errors. The HER2/neu (ERBB2) gene is amplified in approximately 20% of breast cancers, leading to massive overexpression of the HER2 receptor tyrosine kinase on the cell surface — a finding that led directly to the development of trastuzumab (Herceptin). A third mechanism involves chromosomal translocation, best illustrated by the Philadelphia chromosome in chronic myelogenous leukemia (CML), where a reciprocal translocation t(9;22) generates the BCR-ABL fusion protein — a constitutively active tyrosine kinase targeted by imatinib (Gleevec).

Mechanisms of Tumor Suppressor Inactivation

Tumor suppressor genes are inactivated through loss-of-function events. These include nonsense or frameshift mutations that truncate the protein, large deletions that remove the gene entirely, and loss of heterozygosity (LOH) — where the remaining wild-type allele in a heterozygous cell is lost through mitotic recombination, chromosomal nondisjunction, or gene conversion. Crucially, epigenetic silencing via promoter hypermethylation can functionally inactivate a tumor suppressor without altering its DNA sequence, effectively serving as a 'hit' in Knudson's framework. For example, CDKN2A (encoding p16^INK4a) is frequently silenced by methylation in melanoma and pancreatic cancer.

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Dominant-Negative Exception

Some tumor suppressor mutations act in a dominant-negative fashion. Certain missense mutations in TP53 produce a stable but non-functional p53 protein that oligomerizes with wild-type p53 and poisons its transcriptional activity. In such cases, a single mutant allele can effectively neutralize the entire p53 pathway, violating the simple two-hit rule. Some mutant p53 proteins even acquire gain-of-function properties that actively promote invasion and metastasis.

Mechanism	Oncogene Example	Tumor Suppressor Example
Point mutation	KRAS G12V (constitutive activation)	TP53 R175H (loss of DNA binding)
Gene amplification / deletion	HER2 amplification (overexpression)	RB1 deletion (loss of checkpoint)
Chromosomal translocation	BCR-ABL fusion (CML)	Less common; occasionally disrupts gene
Epigenetic silencing	Rare (oncogenes are activated, not silenced)	CDKN2A promoter methylation

Molecular mechanisms of oncogene activation versus tumor suppressor inactivation

SECTION 5

Classification of Oncogenes and Tumor Suppressors by Function

Oncogenes and tumor suppressors are not monolithic categories — they encompass proteins that operate at every level of the signal transduction cascade, from extracellular ligands to nuclear transcription factors. Classifying them by their normal cellular function reveals how cancer co-opts virtually every node in growth regulation.

This diagram maps oncogene products (violet boxes) and tumor suppressor products (pink boxes) to their positions in the signal transduction cascade, from extracellular ligands through cytoplasmic transducers to nuclear effectors. Note how each layer of the cascade contains both positive (oncogene) and negative (tumor suppressor) regulators, illustrating the extensive checks and balances that must be disrupted during carcinogenesis.

Examining the diagram reveals a recurring theme: at every tier of signaling, the cell has built-in redundancy and counter-regulation. Growth factor receptors like HER2 and EGFR relay proliferative signals inward, but their downstream effects are held in check by phosphatases like PTEN (which dephosphorylates PIP₃, opposing PI3K) and GAPs like NF1 (which accelerates RAS GTPase activity, shutting off RAS signaling). In the nucleus, transcription factors like MYC drive cell cycle entry, but their effects are counteracted by p53 and pRb, which can halt the cycle or trigger apoptosis. This layered architecture means that a single mutation rarely suffices — the cell must accumulate hits across multiple nodes.

Gatekeepers vs. Caretakers

Tumor suppressors are further subdivided into two functional classes. Gatekeepers directly regulate cell growth by controlling checkpoints (e.g., RB1, APC) or apoptosis (e.g., TP53). Their loss directly increases cell number. Caretakers maintain genomic stability through DNA repair (e.g., BRCA1, BRCA2, mismatch repair genes). Their loss does not directly promote growth but dramatically increases the mutation rate — a mutator phenotype — accelerating the accumulation of hits in other oncogenes and tumor suppressors. This distinction is clinically important: tumors arising from caretaker defects (e.g., BRCA-mutant breast cancers) often respond to PARP inhibitors that exploit their DNA repair deficiency.

SECTION 6

Worked Example — Tracing Mutations in Colorectal Cancer

The Vogelstein model of colorectal carcinogenesis remains one of the most elegant demonstrations of multistep tumor evolution, illustrating how oncogene activations and tumor suppressor losses cooperate sequentially. Let us trace the progression from normal colonic epithelium to metastatic carcinoma, identifying each gene class involved.

Multistep Carcinogenesis in Colorectal Cancer

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Step 1 — Initiation: Loss of APC (Tumor Suppressor)

The APC gene encodes a component of the β-catenin destruction complex in the Wnt signaling pathway. In normal colonocytes, APC promotes degradation of β-catenin, preventing it from entering the nucleus to activate proliferative target genes. Loss of both APC alleles (two-hit model) stabilizes β-catenin, leading to constitutive Wnt signaling and formation of small, benign adenomatous polyps.

Normal epithelium → Early adenoma (tumor suppressor loss)
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Step 2 — Promotion: Activation of KRAS (Oncogene)

A gain-of-function point mutation in KRAS (e.g., G12V) locks the RAS protein in its active GTP-bound state. This constitutively activates the RAF→MEK→ERK mitogenic cascade, providing sustained proliferative signaling that drives adenoma growth and progression. Only one mutant KRAS allele is sufficient — consistent with its role as a dominant oncogene.

Early adenoma → Intermediate adenoma (oncogene activation)
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Step 3 — Progression: Loss of SMAD4 (Tumor Suppressor)

SMAD4 is a signal transducer in the TGF-β pathway, which normally inhibits epithelial cell proliferation. Biallelic loss of SMAD4 eliminates this growth-inhibitory signal, allowing the adenoma to grow larger and develop more dysplastic features. This is another two-hit tumor suppressor event.

Intermediate adenoma → Late adenoma (tumor suppressor loss)
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Step 4 — Malignant Conversion: Loss of TP53 (Tumor Suppressor)

Loss of both TP53 alleles cripples the cell's ability to arrest the cycle in response to DNA damage, to activate DNA repair, or to undergo apoptosis. With the genome's 'guardian' disabled, chromosomal instability accelerates, and the adenoma transforms into an invasive carcinoma capable of breaching the basement membrane.

Late adenoma → Carcinoma (tumor suppressor loss)
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Step 5 — Metastasis: Additional Hits

Further mutations in genes regulating invasion (e.g., loss of E-cadherin), angiogenesis, and immune evasion enable the carcinoma to metastasize. By this stage, the tumor typically harbors 4–7 driver mutations distributed across both oncogenes and tumor suppressors, as well as dozens to thousands of passenger mutations that do not directly drive growth.

Carcinoma → Metastatic disease (accumulation of driver mutations)

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Key Observation

Notice the pattern: of the four main driver events in the Vogelstein model, three involve tumor suppressor loss (APC, SMAD4, TP53) and one involves oncogene activation (KRAS). This reflects a general principle — most human cancers require more tumor suppressor hits than oncogene hits because each tumor suppressor requires biallelic inactivation, while each oncogene requires only a single activating event.

SECTION 7

Systematic Comparison — Oncogenes vs. Tumor Suppressors

With the mechanistic details established, we can consolidate the core distinctions between these two gene classes in a comprehensive comparison. This table serves as a reference framework and highlights the contrasting genetic behaviors, mutation types, and therapeutic implications of oncogenes versus tumor suppressors.

Feature	Oncogenes	Tumor Suppressors
Normal gene name	Proto-oncogene	Tumor suppressor gene
Normal function	Promote cell growth, division, survival	Inhibit growth, promote apoptosis, maintain genome integrity
Mutation type	Gain-of-function (activating)	Loss-of-function (inactivating)
Alleles required	One mutant allele (dominant)	Both alleles (recessive at cellular level)
Analogy	Stuck accelerator	Cut brake lines
Common mechanisms	Point mutation, amplification, translocation	Deletion, nonsense mutation, LOH, methylation
Hereditary pattern	Rarely inherited (somatic events)	One hit can be inherited (cancer predisposition syndromes)
Therapeutic strategy	Inhibit the overactive protein (e.g., imatinib, trastuzumab)	Harder to drug directly; exploit vulnerabilities (e.g., PARP inhibitors for BRCA loss)
Examples	KRAS, HER2, MYC, BCR-ABL, BRAF, PIK3CA	TP53, RB1, APC, BRCA1, BRCA2, PTEN

Comprehensive comparison of oncogenes and tumor suppressor genes

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CLINICAL PERSPECTIVE

The dominant vs. recessive distinction has direct therapeutic implications. Oncogene products — constitutively active kinases, overexpressed receptors — present druggable targets because you can design small molecules or antibodies that specifically inhibit the aberrant protein. Tumor suppressor loss is inherently harder to target because you cannot easily replace a missing protein in every cell. Instead, clinicians exploit synthetic lethality: if a tumor has lost one DNA repair pathway (e.g., BRCA-mediated homologous recombination), inhibiting a compensatory pathway (e.g., PARP-mediated base excision repair) selectively kills tumor cells while sparing normal cells that retain both pathways.

SECTION 8

Connections to Advanced Cancer Biology

The oncogene–tumor suppressor framework serves as a conceptual scaffold upon which more advanced principles of cancer biology are built. As research has progressed, the original binary classification has been refined by insights from genomics, epigenetics, and tumor microenvironment biology. Understanding these connections prepares students for the nuances encountered in graduate-level oncology and clinical research.

Foundational Concept	Advanced Extension
Oncogene = gain-of-function, dominant	Oncogene addiction: some tumors become so dependent on a single oncogene that its inhibition triggers rapid regression (e.g., BRAF V600E + vemurafenib in melanoma). However, resistance frequently evolves via activation of bypass pathways.
Tumor suppressor = two-hit loss-of-function	Haploinsufficiency: for some tumor suppressors (e.g., PTEN, p27), loss of a single allele reduces protein levels enough to promote tumorigenesis without complete loss — a 'one-and-a-half-hit' model that blurs the clean two-hit paradigm.
Multistep carcinogenesis model	Clonal evolution & tumor heterogeneity: tumors are not monoclonal end-products but dynamically evolving populations. Different subclones within a single tumor may harbor distinct oncogene/tumor suppressor mutations, complicating treatment.
Genetic mutations drive cancer	Epigenetic reprogramming: global DNA hypomethylation, focal CpG island hypermethylation, and histone modifications can activate oncogenes and silence tumor suppressors without genetic mutation. Epigenetic drivers are potentially reversible — a therapeutic opportunity.
Cell-autonomous growth control	Non-cell-autonomous hallmarks: oncogene activation can remodel the tumor microenvironment (e.g., MYC-driven angiogenesis and immune evasion), while tumor suppressor loss can alter immune surveillance. Cancer is increasingly understood as a tissue-level disease.

From foundational concepts to advanced cancer biology

These advanced extensions do not invalidate the oncogene–tumor suppressor framework; rather, they enrich it. The core principle — that cancer requires the cooperative disruption of growth-promoting and growth-restraining pathways — remains the organizing logic of cancer genomics. Modern approaches like precision oncology depend on identifying which specific oncogenes are activated and which tumor suppressors are lost in an individual patient's tumor, then selecting therapies that target those specific vulnerabilities. Concepts like oncogene addiction, synthetic lethality, and epigenetic reversibility all derive their therapeutic logic from this foundational dichotomy.

SECTION 9

Practice Problems

Question 1: CONCEPTUAL

A researcher discovers a novel gene, GeneX. When a single copy of a mutant form of GeneX is introduced into cultured cells, they begin dividing uncontrollably. The wild-type protein normally functions as a cytoplasmic kinase. Is GeneX most likely a proto-oncogene or a tumor suppressor gene? Explain your reasoning based on the genetic behavior observed.

Show answer

GeneX is most likely a proto-oncogene. The key evidence is that a single mutant copy is sufficient to cause uncontrolled division — this is the hallmark of dominant gain-of-function behavior characteristic of oncogenes. Tumor suppressor mutations are typically recessive at the cellular level, requiring loss of both alleles (Knudson's two-hit model). Additionally, the protein's normal function as a cytoplasmic kinase places it in a category commonly associated with proto-oncogenes (e.g., RAF, SRC, ABL), which are components of growth-promoting signaling cascades. The mutation likely locks the kinase in a constitutively active conformation.

Question 2: BASIC CALCULATION

In familial retinoblastoma, a child inherits one defective copy of the RB1 gene. If the spontaneous mutation rate for loss of the remaining wild-type allele in retinal cells is approximately 10⁻⁶ per cell division, and a developing retina undergoes roughly 10⁷ cell divisions, estimate the probability that at least one retinal cell will sustain the second hit. Compare this to the sporadic case, where both hits must occur somatically in the same cell lineage.

Show answer

In the familial case, the expected number of cells sustaining the second hit is approximately 10⁷ × 10⁻⁶ = 10 cells. Using the Poisson approximation, P(at least one event) = 1 − e⁻¹⁰ ≈ 0.99995, meaning retinoblastoma development is virtually certain (and often bilateral). In the sporadic case, two independent mutations must occur in the same cell lineage. The probability of both hits in a single cell line is on the order of (10⁻⁶)² = 10⁻¹², making sporadic retinoblastoma extremely rare, typically unilateral, and presenting later in life. This calculation powerfully illustrates Knudson's two-hit hypothesis and explains why hereditary cancer syndromes involve earlier onset and higher penetrance.

Question 3: INTERMEDIATE

A breast tumor is found to have homozygous deletion of BRCA1 and amplification of MYC. Classify each gene alteration (oncogene activation or tumor suppressor loss), identify the specific molecular mechanism of alteration for each, and predict which therapeutic strategies might exploit these specific mutations.

Show answer

BRCA1 homozygous deletion represents tumor suppressor loss via complete gene deletion (both alleles removed). BRCA1 is a caretaker tumor suppressor involved in homologous recombination repair of double-strand DNA breaks. Its loss creates a DNA repair deficiency. MYC amplification represents oncogene activation via gene amplification, leading to overexpression of the MYC transcription factor that drives cell proliferation and metabolic reprogramming. Therapeutically, BRCA1 loss makes this tumor a candidate for PARP inhibitors (e.g., olaparib), which exploit synthetic lethality — blocking the PARP-mediated backup repair pathway in cells already deficient in homologous recombination. MYC itself remains challenging to target directly, but downstream effectors (e.g., CDK inhibitors, BET bromodomain inhibitors that suppress MYC transcription) represent emerging strategies.

Question 4: APPLIED

A patient with chronic myelogenous leukemia (CML) is treated with imatinib, which targets the BCR-ABL fusion kinase. After initial remission, the patient relapses. Genomic sequencing reveals a T315I point mutation in the ABL kinase domain. Using your knowledge of oncogene biology, explain (a) why imatinib was initially effective, (b) why the T315I mutation confers resistance, and (c) what therapeutic approach would you consider next.

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(a) Imatinib was effective because CML exhibits oncogene addiction — the malignant clone is overwhelmingly dependent on constitutive BCR-ABL kinase activity for survival and proliferation. Blocking BCR-ABL with imatinib removes this essential growth signal, inducing apoptosis in leukemic cells. (b) The T315I 'gatekeeper' mutation substitutes a bulky isoleucine for threonine at a critical residue in the ATP-binding pocket of the ABL kinase domain. This sterically prevents imatinib (and most second-generation inhibitors like dasatinib) from binding, while the kinase retains its catalytic activity. The mutant subclone, pre-existing at low frequency, is positively selected during imatinib treatment. (c) Ponatinib, a third-generation BCR-ABL inhibitor specifically designed to accommodate the T315I mutation's steric constraint, would be the appropriate next-line therapy. This case illustrates how understanding oncogene structure at atomic resolution informs iterative drug design.

Question 5: CRITICAL THINKING

Some missense mutations in TP53 (e.g., R175H, R248W) are classified as both loss-of-function tumor suppressor mutations AND gain-of-function oncogenic mutations. Explain how a single mutation in the same gene can simultaneously exhibit properties of both gene classes. Discuss how this dual nature challenges the traditional oncogene/tumor suppressor dichotomy and what it implies for therapeutic strategy.

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Certain TP53 missense mutations produce a stable protein that simultaneously (1) loses wild-type p53 tumor suppressor function (inability to bind cognate DNA response elements and activate transcription of growth arrest/apoptosis genes like CDKN1A and BAX) and (2) gains new oncogenic activities not present in wild-type p53. The gain-of-function properties arise because the misfolded mutant p53 protein acquires new protein-protein interactions — it can bind and inactivate p63 and p73 (p53 family members that partially compensate for p53 loss), activate novel transcriptional programs promoting invasion, chemoresistance, and metabolic reprogramming, and interact with chromatin remodeling complexes to alter genome-wide gene expression. Furthermore, the mutant protein acts in a dominant-negative manner by oligomerizing with any wild-type p53 produced from the remaining allele, effectively neutralizing it before the second allele is formally lost. This dual nature challenges the traditional binary classification because TP53 mutations cannot be simply classified as tumor suppressor loss — they actively promote malignancy through neomorphic functions. Therapeutically, this means strategies must go beyond attempting to restore p53 function; they must also neutralize the gain-of-function mutant protein. Approaches include small molecules that restore wild-type conformation (e.g., APR-246/eprenetapopt), targeted degradation of mutant p53 via HSP90 inhibitors, and exploitation of vulnerabilities created by the mutant p53 transcriptional program.

SUMMARY

Lesson Summary

Summary

Cancer is fundamentally a disease of disrupted growth control, driven by the cooperative dysfunction of two opposing gene classes. Oncogenes arise from gain-of-function mutations in proto-oncogenes — normal genes encoding growth factors, receptor tyrosine kinases, signal transducers like RAS, and transcription factors like MYC. These mutations act in a dominant fashion — a single mutant allele is sufficient, analogous to a stuck accelerator. Activation mechanisms include point mutations, gene amplification, and chromosomal translocations.

Tumor suppressor genes encode proteins like p53, pRb, APC, BRCA1, and PTEN that enforce checkpoints, promote DNA repair, or trigger apoptosis. Their inactivation requires loss-of-function in both alleles (Knudson's two-hit hypothesis), making them recessive at the cellular level — analogous to failed brakes. Tumor suppressors are further classified as gatekeepers (directly controlling proliferation) and caretakers (maintaining genomic stability). Cancer develops through multistep carcinogenesis — the sequential accumulation of 4–7 driver mutations across both gene classes, as exemplified by the Vogelstein model of colorectal cancer. Therapeutically, oncogene products are directly druggable targets (imatinib, trastuzumab), while tumor suppressor loss is addressed through synthetic lethality strategies such as PARP inhibitors for BRCA-deficient tumors.