Self Sufficiency in Growth Signals Oncogenes

Slide 1 · Self-Sufficiency in Growth Signals: Oncogenes

Molecular mechanisms of autonomous cancer cell growth

Proto-oncogenes • signal transduction • cell-cycle entry

Normal growth control → oncogenic growth autonomy

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Define proto-oncogenes, oncogenes, and constitutively active oncoproteins.

Map normal growth-factor signaling from receptor binding to cell division.

Explain oncogenic activation at ligand, receptor, cytoplasmic, nuclear, and cell-cycle levels.

Connect representative molecular lesions to tumor examples and therapeutic principles.

Slide 3 · Growth autonomy is a hallmark of cancer

Extracellular growth cue

Intracellular signaling

Gene expression

Cell proliferation

Normal tissues regulate proliferation through transient, conditional signaling.

Cancer cells can generate mitogenic drive despite absent external cues.

Oncogenic autonomy does not imply independence from all nutrients or survival signals.

Slide 4 · An oncogene is an activated progrowth gene

An oncogene is an altered gene that drives excessive cell growth.

It arises from a normal proto-oncogene through mutation or overexpression.

Its oncoprotein often signals constitutively or resists normal feedback control.

Cells consequently lose normal dependence on growth-promoting external stimuli.

Slide 5 · Proto-oncogene and oncogene are functionally distinct

Normal proto-oncogene

Oncogene

Physiologic protein supports regulated proliferation.

Expression or activity responds to an appropriate signal.

Activity is time-limited or restrained by negative regulators.

Mutation or overexpression increases progrowth signaling.

Protein may remain active in the absence of a ligand.

Persistent output favors inappropriate cell-cycle progression.

Slide 6 · Cancer-associated oncogenic change is typically gain of function

Proto-oncogene

Activating alteration

Increased protein output

Mitogenic advantage

Change may affect the protein sequence, abundance, or regulatory context.

Constitutive activity is a common outcome, not the only biochemical mechanism.

Slide 7 · Normal mitogenic signaling begins outside the cell

Growth factor binds receptor

Transient receptor activation

Cytoplasmic effectors recruited

Ligand recognition creates a regulated entry point for growth signals.

Multiple cytoplasmic transducers relay or amplify the signal.

Activation normally subsides after the appropriate response.

Slide 8 · Normal mitogenic signaling culminates in division

Signal reaches nucleus

Transcription changes

Cell-cycle proteins increase

Division

Transcription factors and epigenetic alterations support gene expression.

Parallel signals promote survival and metabolic biosynthesis.

Slide 9 · Oncogenic signaling can bypass normal checkpoints

Growth pathway activation

Receptor / ligand level

Excess receptor drive

Cytoplasmic transducers

Persistent signaling

Nuclear / cycle level

Uncontrolled progrowth genes

Slide 10 · Proto-oncogene products span five functional levels

Level

Normal activity

Cancer consequence

Growth factor

Paracrine signal

Autocrine stimulation

Receptor

Ligand-dependent activation

Constitutive kinase activity

Signal transducer

Reversible pathway relay

Persistent kinase or G-protein activity

Transcription factor

Timed growth-gene expression

Continuous gene activation

Cyclin / CDK

Regulated cycle progression

Excessive G₁/S entry

Slide 11 · Several genetic mechanisms activate proto-oncogenes

Point mutation

Changes catalytic or regulatory behavior of a protein.

Gene amplification

Raises gene dosage and typically protein expression.

Chromosomal rearrangement

May create an active fusion or place a gene near strong enhancers.

Overexpression

Excess growth factor or signaling protein increases pathway output.

Slide 12 · Oncogenes and tumor suppressors share signaling networks

Oncogenic activation

Tumor-suppressor loss

Gain of activity in a positive growth regulator.

Example: Activated RAS stimulates downstream kinases.

Excess positive signal accelerates proliferation.

Removes a negative regulator from the same pathway.

Example: Loss of NF1 or PTEN releases signaling restraint.

Loss of inhibition may phenocopy a progrowth mutation.

Slide 13 · Proliferation requires more than DNA synthesis

Sustained oncogenic signaling

Cell-cycle machinery

DNA replication

Protein and membrane synthesis

New cellular structures

Energy / metabolites

Biomass to form daughters

Slide 14 · Growth factors usually act through paracrine circuits

Producer cell

Secreted growth factor

Receptor on neighboring cell

Transient response

Paracrine action separates ligand production from the responsive cell.

Receptor expression helps determine which neighbors can respond.

Slide 15 · Autocrine circuits create a self-stimulating loop

Tumor cell secretes ligand

Same cell expresses receptor

Receptor is stimulated

Growth program is reinforced

Autocrine signaling reduces dependence on growth factor from nearby cells.

Both ligand production and receptor expression are necessary for the loop.

Slide 16 · PDGF–PDGFR illustrates autocrine growth in gliomas

Glioma expresses PDGF

Glioma expresses PDGFR

Autocrine receptor activation

Proliferative stimulus

Gliomas that express both platelet-derived growth factor and its receptor.

This is a ligand-dependent form of growth autonomy, not necessarily a mutated receptor.

Slide 17 · TGF-α–EGFR illustrates another autocrine circuit

Sarcoma produces TGF-α

EGFR is expressed

Ligand binds receptor

Growth signaling

Many sarcomas overexpressing transforming growth factor-α and EGFR.

Ligand abundance and receptor presence together support the autocrine response.

Slide 18 · Receptor tyrosine kinases connect ligand to cytoplasmic signals

Extracellular ligand-binding site

Membrane-spanning receptor

Intracellular kinase domain

Adaptor recruitment

The receptor spans the membrane and contains a cytoplasmic tyrosine kinase.

Tyrosine phosphorylation creates docking sites for signaling factors.

Slide 19 · RTK activation is normally transient

Ligand binding

Receptor dimerization

Autophosphorylation

RAS / PI3K recruitment

The active dimer initiates signaling through phosphorylation.

Downstream activity is conditional on regulated receptor activation.

Slide 20 · Receptor oncogenes evade ligand-dependent control

Activating point mutation

Catalytic activity persists despite absence of growth factor.

Gene amplification

Excess receptors increase signaling capacity and activity.

Gene rearrangement

A fusion may impose constitutive kinase activity.

Common endpoint

Continual mitogenic and survival signaling from receptor pathways.

Slide 21 · EGFR activation can drive lung adenocarcinoma

ERBB1 (EGFR) mutation

Constitutive EGFR kinase

Mitogenic signaling

Tumor growth

Several ERBB1 point mutations in subsets of lung adenocarcinoma.

The molecular lesion supplies a predictive rationale for EGFR kinase inhibition.

Slide 22 · HER2 amplification is a receptor-dose mechanism

ERBB2 gene amplification

HER2 receptor overexpression

Constitutive kinase signaling

Breast carcinoma growth

HER2 is a member of the receptor tyrosine kinase family.

Amplification rather than the example of point mutation drives this textbook association.

Slide 23 · EML4::ALK is an oncogenic fusion kinase

ALK gene rearrangement

EML4::ALK fusion

Constitutive ALK kinase

Lung adenocarcinoma subtype

A chromosome 5 rearrangement creates a chimeric EML4–ALK protein.

ALK activating point mutations also occur in some neuroblastomas.

Slide 24 · Three receptor oncogene patterns are not interchangeable

Gene / protein

Illustrative alteration

Tumor example

ERBB1 / EGFR

Activating point mutation

Lung adenocarcinoma

ERBB2 / HER2

Gene amplification

Breast carcinoma

ALK

Rearrangement → fusion

Lung adenocarcinoma

ALK

Activating point mutation

Subset of neuroblastomas

Slide 25 · RTK addiction creates a therapeutic vulnerability

Driver RTK signaling

Growth + survival support

Selective kinase blockade

Growth arrest / regression

In tumors bearing the target alteration, receptor inhibition can suppress growth.

Tumor regression also reflects loss of prosurvival signaling.

Slide 26 · Pathway inhibition can promote tumor-cell apoptosis

Before inhibitor

After effective inhibitor

Activated RTK supports cell proliferation.

Parallel pathway activity contributes to survival.

Cells remain dependent on oncogenic signaling.

Kinase activity is suppressed.

Progrowth and survival signals decline.

Growth inhibition and apoptosis may follow.

Slide 27 · Acquired resistance limits advanced-cancer control

Sensitive tumor clone

Targeted kinase inhibitor

Resistant surviving subclones

Disease progression

Response to an inhibitor does not guarantee eradication of every tumor cell.

Selection of genetically heterogeneous subclones provides a route to resistance.

Slide 28 · EGFR inhibitor resistance can alter drug binding

Mutant EGFR-driven cancer

EGFR inhibitor exposure

New EGFR alteration

Impaired inhibitor binding

Acquired EGFR mutations that interfere with inhibitor binding.

The altered receptor can preserve signaling despite pharmacologic blockade.

Slide 29 · MET amplification can bypass EGFR inhibition

EGFR signaling blocked

MET copy number increases

Alternative RTK signal

Downstream growth restored

MET encodes another receptor tyrosine kinase.

Amplification creates a bypass pathway rather than restoring drug binding to EGFR.

Slide 30 · Tumor heterogeneity supplies resistant subclones

Heterogeneous tumor population

Drug-sensitive clone

Depleted by therapy

EGFR-altered resistant clone

Survives target blockade

MET-amplified clone

Signals around target

Slide 31 · RAS proteins are membrane-associated molecular switches

Growth-factor receptor

GDP–RAS (off)

GTP–RAS (on)

Effector activation

Human RAS proto-oncogenes include HRAS, KRAS, and NRAS.

Guanosine nucleotide exchange regulates the active signaling state.

Slide 32 · RAS normally cycles between GDP and GTP states

GDP-bound RAS

GTP-bound RAS

Quiescent, signal-off state.

Predominates after GTP hydrolysis.

Does not relay the same active mitogenic output.

Active, signal-transmitting state.

Generated by receptor-coupled nucleotide exchange.

Engages downstream growth-control effectors.

Slide 33 · GAP proteins terminate active RAS signaling

RAS bound to GTP

GTPase-activating protein

GTP hydrolysis to GDP

Inactive RAS

RAS has intrinsic GTPase activity accelerated by GAPs.

GAPs act as brakes that limit duration of RAS activation.

Slide 34 · RAS point mutations can lock the switch on

RAS point mutation

Defective GTP hydrolysis

Persistent GTP–RAS

Continuous progrowth signal

Mutant RAS resists return to the GDP-bound state.

The resulting signal can remain active without repeated receptor stimulation.

Slide 35 · NF1 loss demonstrates the role of a pathway brake

NF1 encodes neurofibromin

Neurofibromin acts as GAP

NF1 loss weakens GTP hydrolysis

RAS signaling persists

NF1 is a tumor-suppressor gene, not a proto-oncogene.

Germline loss predisposes to neurofibromatosis type 1.

Slide 36 · Upstream RTK and RAS drivers are often alternative

RTK-driven clone

RAS-driven clone

Activating alteration at the receptor level.

RAS and downstream signals follow receptor activation.

An RTK-directed inhibitor may match the driver.

Oncogenic RAS provides a downstream input.

RTK activating mutations are usually absent in the dominant clone.

Blocking the receptor may not extinguish mutant RAS.

Slide 37 · RAS mutations occur across multiple tumor lineages

RAS family member

Illustrative tumor association

Mode

KRAS

Colorectal, lung, pancreatic tumors

Point mutation

HRAS

Bladder and kidney tumors

Point mutation

NRAS

Melanoma, hematologic malignancies

Point mutation

Slide 38 · RAS feeds two major progrowth signaling arms

Active RAS

RAF → MAPK

PI3K → AKT

Progrowth transcription

Protein synthesis + survival

Integrated growth program supports cell division

Slide 39 · RAF–MAPK transmits growth signals to the nucleus

RAS–GTP

RAF kinase

MAPK cascade

Transcription-factor activation

RAF proteins are serine/threonine kinases.

Activation of transcription factors increases expression of progrowth genes.

Slide 40 · BRAF mutations activate the MAPK cascade

Activating BRAF mutation

RAF pathway active

Downstream kinases activated

Growth-gene expression

BRAF activation with hairy cell leukemia and melanoma.

Mutations near the top of signaling cascades can yield pronounced progrowth effects.

Slide 41 · PI3K–AKT couples signals to biomass and survival

Activated receptor / RAS

PI3K activation

AKT signaling

Growth + survival effectors

PI3K operates near plasma membrane signaling complexes.

AKT regulates protein synthesis, apoptosis-related factors, and other outputs.

Slide 42 · PTEN imposes negative control on PI3K signaling

PTEN intact

PTEN function lost

PTEN restrains the PI3K pathway.

Negative regulation limits pathway activation.

Growth and survival output remains regulated.

PI3K signaling is less restrained.

AKT pathway output can increase.

Oncogenic pathway activation can arise without PI3K gain of function.

Slide 43 · AKT signaling supports an anabolic phenotype

AKT signaling hub

MTOR-linked control

Protein synthesis

Anti-apoptotic substrates

Enhanced survival

Other kinase targets

Integrated growth response

Slide 44 · MAPK and PI3K/AKT have distinct emphases

Branch

Representative components

Major teaching emphasis

RAF / MAPK

RAS → RAF → MAPK

Transcriptional progrowth activation

PI3K / AKT

PI3K → AKT → mTOR

Biosynthesis and cell survival

Shared context

Both downstream of RTK/RAS

Coordinated cell growth

Slide 45 · Mutant KRAS is targetable in selected settings

KRAS G12C mutation

Altered protein structure

Allele-directed inhibitor

Growth pathway suppressed

The source describes approved agents targeting KRAS with glycine→cysteine substitution at codon 12.

A specific molecular variant—not KRAS mutation in general—defines this therapeutic example.

Slide 46 · Targeting RAF or PI3K is a pathway-level strategy

BRAF inhibitor strategy

PI3K inhibitor strategy

Targets an activated downstream kinase.

Substantial responses in some advanced melanomas.

Response depends on relevant tumor biology.

Intervenes in a separate kinase cascade.

Some PI3K isoform inhibitors are approved in selected malignancies.

Pathway perturbation must be molecularly contextualized.

Slide 47 · Nonreceptor kinases need no transmembrane domain

Cytoplasmic / nuclear kinase

Activating mutation or fusion

Constitutive catalytic activity

Mitogenic pathway output

Nonreceptor tyrosine kinases are normally located inside the cell.

Oncogenic activation can stimulate pathways overlapping those of RTKs.

Slide 48 · BCR::ABL is a fusion oncogene

ABL locus on chr 9

BCR locus on chr 22

BCR::ABL rearrangement

Constitutive ABL kinase

The fusion is characteristic of chronic myeloid leukemia.

It also occurs in a subset of acute lymphoblastic leukemias.

Slide 49 · The Philadelphia chromosome encodes BCR::ABL

Rearrangement

Functional consequence

ABL is translocated from chromosome 9 to chromosome 22.

ABL joins the BCR gene.

The Philadelphia chromosome is derived from chromosome 22.

BCR contributes self-association capacity.

The chimeric ABL kinase becomes constitutively active.

Excess signaling supports leukemic proliferation.

Slide 50 · Fusion-partner self-association activates ABL

BCR::ABL protein

BCR-driven self-association

ABL kinase unlocked

Persistent signaling

Fusion protein formation removes normal control over ABL catalytic output.

This mechanism recurs among multiple oncogenic kinase fusions.

Slide 51 · CML exemplifies oncogene addiction

BCR::ABL initiates CML

Leukemia depends on its signal

Kinase inhibitor blocks driver

Clinical remission

A highly dominant oncogenic driver creates a therapeutic dependence.

CML response to BCR–ABL inhibition as a central example.

Slide 52 · Residual stemlike cells can outlast targeted therapy

BCR::ABL kinase inhibited

Proliferating cells suppressed

Rare transformed stemlike cells remain

Disease may recur after withdrawal

A clinical remission need not equal eradication of all leukemia-initiating cells.

Persistence of cells less dependent on BCR–ABL signaling for survival.

Slide 53 · JAK2 mutations can activate nonreceptor signaling

JAK2 regulatory mutation

Loss of autoinhibition

Persistent JAK/STAT signaling

Myeloid proliferation

JAK2 relays signals from cytokine receptors lacking intrinsic kinase domains.

The source cites polycythemia vera and related myeloid neoplasms.

Slide 54 · JAK/STAT links cytokine receptors to transcription

Growth factor / cytokine receptor

JAK2 activation

STAT transcription factors

Growth-related gene expression

Mutant JAK2 can reduce reliance on hematopoietic growth signals such as erythropoietin.

The resulting transcriptional program promotes expansion of affected myeloid cells.

Slide 55 · Mitogenic pathways converge on nuclear regulators

Deregulated growth signaling

RAS / MAPK

Growth-related TFs

JAK / STAT

STAT target genes

Other oncogenic pathways

MYC and other targets

Slide 56 · MYC is a rapid, normally transient response gene

Growth factor

RAS / MAPK response

MYC rapidly induced

Timed growth response

MYC expression is normally controlled at transcription, translation, and protein stability levels.

Persistent MYC expression drives a broad progrowth transcriptional program.

Slide 57 · MYC stimulates cell-cycle and growth programs

MYC upregulation

Cyclin D and other targets

G₁ progression

Proliferative advantage

MYC induces many genes involved in cell growth.

Its output extends beyond simple acceleration of DNA replication.

Slide 58 · MYC increases the cell’s protein-making capacity

MYC activity

More rRNA transcription

More ribosome biogenesis

Enhanced protein synthesis

Ribosomal RNA expression and processing are MYC-regulated programs.

Biosynthetic capacity helps a dividing cell produce daughter-cell biomass.

Slide 59 · MYC supports cancer-associated metabolic reprogramming

MYC upregulation

Glycolytic and glutamine programs

Metabolic intermediates

Macromolecule synthesis

MYC promotes production of precursors for proteins, lipids, and nucleic acids.

This program with the Warburg effect.

Slide 60 · MYC can contribute to immortalization and stemness

Telomerase connection

Cell-state connection

MYC may increase telomerase expression in some contexts.

Telomerase contributes to extended replicative capacity.

MYC participates in somatic-cell reprogramming.

The source discusses a possible contribution to cancer stemness.

Slide 61 · MYC translocation alters enhancer control

MYC relocated by translocation

Antigen-receptor enhancer nearby

MYC overexpression

Lymphoid tumor growth

Burkitt lymphoma characteristically involves an MYC translocation.

Regulatory enhancers activate MYC expression inappropriately.

Slide 62 · MYC family amplification increases gene dosage

Gene

Alteration

Illustrative tumor

MYC

Gene amplification

Breast, colon, and lung tumors

NMYC

Amplification

Neuroblastoma

LMYC

Amplification

Small-cell lung carcinoma

Slide 63 · Several upstream pathways converge on MYC

Oncogenic signaling

RAS / MAPK

MYC expression

Notch or Wnt

Lineage-dependent MYC effects

Hedgehog

Context-specific MYC output

Slide 64 · Cyclin–CDK complexes drive cell-cycle progression

Cyclin D produced

CDK4 / CDK6 binds cyclin

RB becomes phosphorylated

G₁/S progression

Cyclins are regulated cyclically; CDKs are activated by cyclin binding.

D cyclins and CDK4 act at the key G₁ restriction point.

Slide 65 · G₁/S is an important oncogenic control point

Properly controlled

Oncogenic disturbance

Growth cues regulate cyclin D–CDK activity.

RB restrains E2F activity in its hypophosphorylated state.

Checkpoint signals prevent inappropriate S-phase entry.

Excess cyclin D or CDK4 increases kinase drive.

RB phosphorylation releases E2F-dependent programs.

G₁/S progression becomes less dependent on normal cues.

Slide 66 · Cyclin D gene activation promotes unchecked G₁ progression

CCND1 rearrangement / amplification

Excess cyclin D1

Higher cyclin D–CDK activity

G₁/S entry

CCND1 translocation is a textbook example in mantle cell lymphoma.

Amplification also occurs in some breast and esophageal cancers.

Slide 67 · CDK4 amplification is a cell-cycle oncogene mechanism

CDK4 gain of function

Excess CDK4 activity

Increased RB phosphorylation

Cell-cycle acceleration

CDK4 amplification with melanoma, sarcoma, and aggressive glial tumors.

CDK4/6-targeted inhibitors illustrate a therapeutic consequence in selected breast cancers.

Slide 68 · The same growth program can be deregulated at many levels

Signaling level

Representative lesion

Common output

Growth factor

PDGF autocrine loop

Persistent receptor stimulus

Receptor

EGFR mutant / ERBB2 gain

Constitutive kinase input

Cytoplasmic

KRAS / BRAF / PI3K

Progrowth signaling

Nuclear

MYC overexpression

Growth-gene transcription

Cell cycle

CCND1 / CDK4 activation

Unchecked G₁/S entry

Slide 69 · Molecular alteration predicts where inhibition may act

Driver example

Major pathway position

Therapeutic logic

Mutant EGFR

Receptor kinase

Inhibit altered EGFR activity

EML4::ALK

Fusion receptor kinase

Block ALK kinase

BCR::ABL

Fusion nonreceptor kinase

Block ABL kinase

Mutant BRAF

MAPK arm

Inhibit activated RAF

KRAS G12C

RAS signaling node

Allele-specific RAS targeting

Slide 70 · Application: EGFR mutation and progressive lung cancer

A lung adenocarcinoma harbors an activating ERBB1 mutation and initially regresses with an EGFR inhibitor. After a period of response, the tumor progresses, and MET amplification is identified.

Which pathway-level explanation best accounts for the progression?

MET supplies alternative receptor signaling downstream.

A new autocrine growth factor is necessarily present.

The tumor has become biologically incapable of growth.

Slide 71 · EGFR resistance: A bypass, not loss of growth autonomy

EGFR inhibitor

EGFR output reduced

MET amplification

RTK signaling rerouted

MET-driven bypass can restore downstream progrowth signaling.

Tumor evolution explains why the initial response does not guarantee cure.

Slide 72 · Application: A constitutive fusion kinase in leukemia

A patient has chronic myeloid leukemia with a BCR::ABL fusion. A tyrosine kinase inhibitor markedly suppresses the proliferative population, but rare fusion-positive stemlike cells persist.

Which two Robbins concepts are illustrated?

Oncogene addiction to BCR::ABL signaling.

Incomplete eradication of a stemlike residual compartment.

Mandatory loss of every tumor-suppressor gene.

Slide 73 · CML response illustrates dependence and persistence

Strong clinical response

Limits of molecular suppression

BCR::ABL is a dominant driver.

Kinase inhibition suppresses proliferating leukemia.

Oncogene addiction creates high drug sensitivity.

Some rare stemlike cells remain.

Residual cells may not require the same kinase signal to survive.

Discontinuation can be followed by recurrent disease.

Slide 74 · Integrative framework: Signals, circuitry, output

Growth factor / receptor

RAS–MAPK and PI3K–AKT

MYC / cyclin D–CDK

Growth + division

Oncogenic alterations may act at any step of the normal signaling chain.

Mutations in negative regulators can produce similar pathway activation.

Therapeutic sensitivity depends on the operative molecular driver and tumor context.

Slide 75 · Core principles to retain

Oncogenes represent gain of progrowth function in normal cellular genes.

Growth autonomy can be generated by ligands, receptors, switches, kinases, transcription factors, or cyclin–CDK components.

MAPK transcriptional signals and PI3K–AKT biosynthetic/survival signals converge on sustained growth.

Targeted inhibition exposes dependencies; Genetic heterogeneity and persistent cells can limit durability.

Slide 76 · Primary reference and teaching scope

This lecture is grounded in the specified 2026 Robbins textbook chapter.

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 7, Neoplasia.

Self-Sufficiency in Growth Signals: Oncogenes; Oncoproteins and Cell Growth; Growth Factors; Growth Factor Receptors.

Downstream Components of the Receptor Tyrosine Kinase Signaling Pathway; Nonreceptor Tyrosine Kinases; Transcription Factors; MYC; Cyclins and Cyclin-Dependent Kinases.

Mechanism schematics are original, editable PowerPoint constructions; no histologic or patient specimens are depicted.