Growth Factor Receptors

Slide 1 · Growth Factor Receptors

Receptor tyrosine kinase activation, oncogenic alterations and therapeutic resistance

Ligand sensing

Oncogenic activation

Cancer growth

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how a normal receptor tyrosine kinase converts ligand binding into a transient signal.

Distinguish point mutation, gene amplification, and rearrangement as RTK oncogenic mechanisms.

Link specific receptor lesions to the example tumors and targeted-therapy implications.

Explain why receptor-directed therapy can select resistant tumor subclones.

Slide 3 · Receptors are one class of proto-oncogene products

Proto-oncogenes encode growth factors, receptors, signal transducers, transcription factors, or cell-cycle regulators.

Receptor oncogenes act near the cell surface, upstream of intracellular growth programs.

Gain of receptor activity reduces dependence on normal extracellular control.

Growth factor

Receptor

Signal transducer

Nuclear program

Slide 4 · Why receptor tyrosine kinases matter in cancer

Many oncogenes encode growth factor receptors.

Receptor tyrosine kinases (RTKs) are among the most important growth factor receptors in oncogenesis.

The same signaling machinery ordinarily supports regulated cell proliferation and survival.

Extracellular cue

RTK activation

Cellular response

Slide 5 · An RTK crosses the plasma membrane

Extracellular domain recognizes a specific growth factor.

Cytoplasmic domain contains tyrosine kinase activity.

The receptor links an external ligand to intracellular signaling machinery.

EXTRACELLULAR

CYTOPLASM

Growth factor–binding domain

Kinase domain

Slide 6 · Ligand binding begins a normal RTK signal

Activation normally begins with a matching growth factor binding its receptor.

Receptor engagement triggers a conformational change.

The signal is ligand-dependent in its physiologic state.

EXTRACELLULAR

CYTOPLASM

GF

Ligand binding

Slide 7 · Ligand engagement favors the active dimer

Activated receptors adopt an active dimeric state.

Dimer formation places intracellular kinase domains in an activation-competent arrangement.

Dimerization is a key step between ligand recognition and signaling.

EXTRACELLULAR

CYTOPLASM

GF

Active dimer

Slide 8 · Autophosphorylation creates signaling sites

Activated RTKs phosphorylate tyrosine residues on intracellular receptor tails.

Phosphotyrosines form molecular recruitment sites for downstream proteins.

Kinase activation is therefore coupled to assembly of a signaling complex.

EXTRACELLULAR

CYTOPLASM

P

P

P

P

GF

Autophosphorylation

Slide 9 · Phosphorylated tails recruit signaling proteins

RAS-linked signaling molecules and PI3K-associated signaling are recruited downstream.

Receptor phosphorylation creates docking sites rather than directly entering the nucleus.

The signal is propagated through additional cytoplasmic components.

EXTRACELLULAR

CYTOPLASM

P

P

P

P

GF

RAS

PI3K

P = phosphotyrosine

Slide 10 · The normal signaling sequence is ordered

Ligand recognition precedes the active receptor conformation.

Tyrosine phosphorylation precedes recruitment of downstream proteins.

Downstream signals ultimately regulate transcription and cell-cycle entry.

Ligand binding

Dimer / kinase

Phosphotyrosines

Cell response

Slide 11 · RTK activation is normally transient

Physiologic activation depends on an external growth factor.

Normal receptor

Oncogenic receptor

Requires ligand to activate

Can be active without ligand

Transient activation

Persistent kinase activity

External growth control

Relative autonomy from external cues

Slide 12 · Mitogenic signaling needs more than DNA replication

Normal growth signaling promotes cell-cycle entry and progression.

Growth also requires synthesis of membranes, proteins, and other macromolecules.

The associated program coordinates biosynthesis and cell survival.

RTK signal

Cell-cycle genes

Biosynthesis

Cell growth

Slide 13 · RTK signaling can also support survival

Growth signaling can augment cell survival, not simply accelerate division.

Consequently, inhibiting a driver RTK may trigger apoptosis.

This dual effect helps explain tumor regression following effective therapy.

Oncogenic RTK

Growth + survival

Tumor persistence

Slide 14 · An oncogenic RTK can signal without ligand

Activating genetic lesions generate constitutive tyrosine kinase activity.

Mitogenic signals continue even without growth factor.

The receptor becomes an oncoprotein rather than a physiologically regulated switch.

EXTRACELLULAR

CYTOPLASM

P

P

P

P

No ligand required

Persistent kinase activity

Slide 15 · Constitutive signaling removes a normal dependency

Normal RTKs couple signal strength to the availability of growth factor.

Normal control

Tumor-associated escape

Ligand needed for activation

Ligand-independent activity

Short-lived activation

Persistent downstream signaling

Proliferation responds to cues

Proliferation can become autonomous

Slide 16 · Three genomic routes converge on RTK activation

Point mutation: Alters receptor function.

Amplification: Increases copy number and receptor abundance.

Rearrangement: Can create an oncogenic fusion kinase.

Point mutation

Gene amplification

Gene rearrangement

Slide 17 · Point mutations can activate the receptor kinase

A nucleotide-level alteration can increase receptor activity.

An activated kinase can signal without normal ligand control.

Examples: ERBB1 in lung adenocarcinoma and KIT in gastrointestinal stromal tumors.

RTK gene

Normal coding sequence

Sequence alteration

Constitutive kinase

Slide 18 · Gene amplification raises receptor abundance

Additional gene copies can drive marked receptor overexpression.

, ERBB2 amplification is the canonical breast carcinoma example.

Excess HER2 is associated with constitutive tyrosine kinase activity.

RTK gene

Single gene locus

GENE

GENE

GENE

GENE

More receptor protein

Slide 19 · Rearrangement can generate a fusion oncoprotein

Chromosomal rearrangement can join portions of different genes.

Fusion can retain an active kinase component while changing normal regulation.

The EML4::ALK fusion in lung adenocarcinoma is a central example.

RTK gene

EML4 segment

ALK kinase segment

Rearranged / fusion locus

Oncogenic kinase signal

Slide 20 · Mechanism should not be confused with tumor type

Genetic event

Receptor example

Tumor association

Point mutation

ERBB1 / EGFR

Lung adenocarcinoma

Gene amplification

ERBB2 / HER2

Breast carcinoma

Gene rearrangement

EML4::ALK

Lung adenocarcinoma

Slide 21 · EGFR is encoded by ERBB1

ERBB1 is the proto-oncogene name; EGFR is its receptor product.

EGFR belongs to the receptor tyrosine kinase family.

Oncogenic EGFR activity derives from activating ERBB1 mutations in the highlighted lung subset.

ERBB1

EGFR protein

Slide 22 · Mutant EGFR bypasses ligand dependence

Several different ERBB1 point mutations can activate the EGFR kinase.

These lesions are associated with persistent downstream growth signals.

No single universal EGFR mutation is specified in the source passage.

EXTRACELLULAR

CYTOPLASM

P

P

P

P

No ligand required

Mutant EGFR

Slide 23 · EGFR-mutant lung adenocarcinoma is a molecular subset

Only a subset of lung adenocarcinomas harbor the highlighted ERBB1 mutations.

This is a molecular mechanism, not a distinct histologic morphology established by the source excerpt.

Genotype helps explain why selected tumors respond to EGFR-directed inhibition.

Lung adenocarcinoma

ERBB1 mutation

Activated EGFR

Targetable kinase

Slide 24 · A receptor mutation is not the same as excess ligand

Autocrine growth factor production increases availability of an extracellular stimulus.

Autocrine ligand loop

Mutant receptor

Cell provides its own ligand

Receptor kinase is activated genetically

Ligand–receptor interaction remains relevant

Ligand may no longer be required

Example: PDGF / PDGFR in gliomas

Example: mutant EGFR in lung cancer

Slide 25 · The EGFR target is the altered kinase

EGFR-directed inhibitors suppress kinase signaling in susceptible EGFR-mutant lung adenocarcinomas.

Responses establish that the mutant pathway can be functionally important to tumor survival.

The therapeutic principle is pathway dependency, not guaranteed cure.

Activating ERBB1 lesion

EGFR signaling

EGFR inhibition

Slide 26 · HER2 is encoded by ERBB2

ERBB2 is a distinct receptor tyrosine kinase gene within the ERBB family.

Its protein product is HER2.

ERBB2 amplification rather than point mutation in selected breast carcinomas.

ERBB2

HER2 protein

Slide 27 · ERBB2 amplification changes gene dosage

More copies of ERBB2 can produce more HER2 receptor protein.

The source connects receptor overexpression to persistent kinase activity.

Gene dosage and receptor activation are mechanistically linked in this example.

ERBB2

Single gene locus

GENE

GENE

GENE

GENE

More receptor protein

Slide 28 · HER2 overexpression is biologically consequential

Excess HER2 is associated with constitutive tyrosine kinase signaling.

Such signaling supports cell proliferation and survival.

The same pathway is a rationale for HER2-directed agents.

ERBB2 amplification

HER2 overexpression

Constitutive signaling

Slide 29 · ERBB2 amplification occurs in certain breast cancers

The textbook does not state that all breast carcinomas amplify ERBB2.

This lesion defines a biologically significant subgroup.

An amplified oncogenic driver can create vulnerability to HER2 inhibition.

Breast carcinoma

ERBB2 amplification

HER2 dependency

Therapy rationale

Slide 30 · HER2 inhibition can induce tumor regression

Antibodies and other HER2-inhibiting agents can produce clinical responses.

Growth arrest alone does not explain the observed activity.

Apoptosis after blockade illustrates the survival contribution of RTK signaling.

HER2 inhibition

Less growth signaling

Apoptosis / regression

Slide 31 · EGFR and HER2 illustrate different oncogenic routes

Feature

EGFR example

HER2 example

Gene

ERBB1

ERBB2

Dominant lesion described

Activating point mutation

Amplification

Illustrative tumor

Lung adenocarcinoma

Breast carcinoma

Targeted therapy concept

EGFR inhibition

HER2 inhibition

Slide 32 · ALK is another receptor tyrosine kinase oncogene

ALK is a receptor tyrosine kinase gene.

Rearrangements as a common ALK oncogenic mechanism.

In a different tumor context, activating ALK point mutations also occur.

ALK rearrangement

ALK point mutation

Slide 33 · EML4::ALK arises from a chromosome 5 rearrangement

A deletion on chromosome 5 joining segments of EML4 and ALK.

The fusion gene produces an EML4–ALK chimeric protein.

The resulting protein has constitutive tyrosine kinase activity.

EML4::ALK

EML4 segment

ALK kinase segment

Rearranged / fusion locus

Oncogenic kinase signal

Slide 34 · A fusion kinase differs from a full-length RTK

The genomic fusion modifies the native gene context.

Native ALK receptor

EML4–ALK fusion product

Encoded by the ALK gene

Encoded by a rearranged fusion gene

Growth-factor receptor context

Chimeric kinase context

Normally controlled signaling

Constitutive kinase activity

Slide 35 · EML4::ALK identifies a lung cancer subgroup

An ALK fusion occurs in a subset of lung adenocarcinomas.

The fusion is a molecular driver with constitutive kinase activity.

ALK inhibitors can yield responses in tumors harboring the relevant fusion.

Lung adenocarcinoma

EML4::ALK fusion

Activated ALK kinase

ALK inhibition

Slide 36 · ALK point mutations are relevant to neuroblastoma

Activating ALK point mutations also act as oncogenic events.

A subset of neuroblastomas.

Thus, the same kinase gene can be activated through distinct alterations in different tumors.

ALK

Normal coding sequence

Sequence alteration

Constitutive kinase

Slide 37 · The oncogenic lesion can depend on cellular context

ALK alteration

Example tumor

Molecular consequence

Rearrangement / fusion

Lung adenocarcinoma

Constitutive fusion kinase

Rearrangement / translocation

Certain lymphomas

Constitutive ALK signaling

Activating point mutation

Neuroblastoma

Activated ALK kinase

Slide 38 · Other receptor genes broaden the oncogene spectrum

Receptor gene

Activation reported in Table 7.5

Example tumor

FLT3

Point mutation or small duplications

Leukemia

RET

Point mutation

MEN 2A / MEN 2B; familial medullary thyroid carcinoma

PDGFRB

Amplification or translocation

Gliomas; leukemias

KIT

Point mutation

Gastrointestinal stromal tumors

Slide 39 · FLT3: Small sequence alterations can activate a kinase

FLT3 encodes a receptor tyrosine kinase.

Oncogenic alterations include point mutation or small duplications.

Table 7.5 associates these lesions with leukemia.

FLT3

Normal coding sequence

Sequence alteration

Constitutive kinase

Slide 40 · RET: Point mutations in hereditary endocrine tumors

RET encodes a neurotrophic factor receptor tyrosine kinase.

RET point mutations with MEN 2A, MEN 2B, and familial medullary thyroid carcinoma.

This is an example of a receptor oncogene implicated in inherited cancer syndromes.

RET point mutation

MEN 2 syndromes

Medullary thyroid carcinoma

Slide 41 · PDGFRB: Amplification and translocation

PDGFRB encodes a platelet-derived growth factor receptor.

Its oncogenic modes in the source table include amplification and translocation.

The associated disease examples are gliomas and leukemias.

PDGFRB

Receptor locus A

Partner locus B

Rearranged / fusion locus

Oncogenic kinase signal

Slide 42 · KIT: Activating receptor point mutations

KIT encodes the receptor for KIT ligand.

Point mutation is the activation mechanism shown in the source table.

Gastrointestinal stromal tumors, seminomas, and leukemias are listed associations.

KIT mutation

Constitutive signal

Associated neoplasms

Slide 43 · An alteration–tumor matrix prevents overgeneralization

Gene

Mutation

Amplification

Rearrangement

ERBB1

Yes (lung)

Not listed

Not listed

ERBB2

Not highlighted

Yes (breast)

Not listed

ALK

Yes (neuroblastoma)

Not listed

Yes (lung; lymphoma)

PDGFRB

Not listed

Yes

Yes

KIT

Yes

Not listed

Not listed

Slide 44 · Activated RTKs converge on cytoplasmic effectors

Autophosphorylated receptors recruit proteins connected to RAS and PI3K signaling.

Different RTK oncogenes can converge on shared downstream growth programs.

The cellular consequence depends on receptor context and its downstream signaling.

Activated RTK

RAS / PI3K

Growth + survival

Slide 45 · RAS links receptors to mitogenic signaling

The adjacent Robbins section places RAS immediately downstream of activated RTKs.

RAS conveys signals toward the RAF–MAPK arm.

This pathway is one route to transcription of progrowth genes.

RTK

RAS

RAF / MAPK

Progrowth genes

Slide 46 · PI3K links receptor signals to growth and survival

PI3K is recruited in RTK signaling and feeds into AKT-associated pathways.

This arm supports growth-related biosynthesis and cell survival.

Its outputs help explain the consequences of RTK blockade.

RTK

PI3K

AKT / mTOR

Growth + survival

Slide 47 · Two major downstream arms have distinct emphases

RTK signaling can stimulate RAS–MAPK and PI3K–AKT signaling.

RAS → RAF → MAPK

PI3K → AKT / mTOR

Progrowth transcriptional signaling

Growth-related metabolism and synthesis

Cell-cycle progression

Cell survival and growth

Both can respond to activated RTKs

Both can respond to activated RTKs

Slide 48 · Receptor oncogenes sit upstream of transcriptional change

Constitutive kinase activity initiates repeated cytoplasmic signaling.

Signal cascades alter transcriptional programs.

Proliferation and survival follow from the combined cell-state changes.

Oncogenic RTK

Signaling cascade

Gene expression

Cell growth

Slide 49 · Targeted therapy tests driver dependency

If a cancer depends on a constitutively active kinase, inhibiting it may suppress tumor growth.

Responses to EGFR, HER2, and ALK inhibitors support the causal importance of those receptors.

Drug response is functional evidence; It does not imply permanent tumor eradication.

Driver kinase

Pharmacologic blockade

Clinical response

Slide 50 · The therapeutic intervention can act at the receptor

HER2-targeting antibodies and drugs interfere with HER2 activity.

EGFR inhibitors target activated EGFR signaling in appropriately altered lung cancers.

ALK inhibitors suppress ALK signaling in tumors with the relevant fusion.

Altered receptor

Targeted inhibitor

Reduced output

Slide 51 · Blocking a driver RTK may induce apoptosis

Receptor signaling normally supports survival as well as division.

Suppression of an essential oncogenic RTK can remove survival signals.

Tumor regression can therefore follow cell death, not merely slower proliferation.

Reduced mitogenesis

Reduced survival

Tumor regression

Slide 52 · Therapeutic response is not equivalent to cure

Inhibitors can elicit major responses in selected receptor-driven tumors.

Initial dependency

Escape under treatment

Dominant clone relies on RTK

Surviving subclone bypasses inhibition

Kinase inhibitor blocks key signal

Acquired alterations restore growth

Tumor shrinks

Resistant disease may emerge

Slide 53 · An EGFR alteration can obstruct drug binding

Lung cancers may acquire further EGFR mutations during EGFR inhibitor treatment.

Some such alterations prevent the inhibitor from binding effectively.

An active pathway can persist despite drug exposure.

EGFR resistance

Normal coding sequence

Sequence alteration

Constitutive kinase

Slide 54 · MET amplification provides an alternative signaling route

MET encodes another receptor tyrosine kinase.

Amplification of MET is a resistance mechanism described for EGFR-inhibited lung cancers.

An alternative driver can bypass the inhibited EGFR pathway.

EGFR inhibited

MET amplified

Bypass signaling

Slide 55 · Tumor heterogeneity makes resistance plausible

Tumors may contain genetically distinct subclones.

Treatment suppresses susceptible cells but favors survival of resistant populations.

The surviving population can repopulate the tumor.

Mixed subclones

Targeted treatment

Resistant survivors

Progression

Slide 56 · Two resistance routes are mechanistically distinct

Mechanism

Molecular example

Why the inhibitor fails

On-target alteration

Further EGFR mutation

Drug cannot bind the altered target

Bypass activation

MET gene amplification

Alternative RTK supports signaling

General principle

Subclonal diversity

Drug selects a non-susceptible cell population

Slide 57 · Genetic mechanism is not identical to receptor abundance

ERBB2 amplification predicts increased gene dosage and receptor overexpression in the source example.

Mutation

Amplification / fusion

Changes protein function

Changes dosage or gene architecture

EGFR and KIT examples

HER2 dosage; ALK fusion examples

Requires genotype-aware interpretation

Requires mechanism-aware interpretation

Slide 58 · Clinicopathologic interpretation must remain specific

Tumor context

Molecular finding

Supported inference

Lung adenocarcinoma

Activating ERBB1 mutation

EGFR-driven signaling may be targetable

Breast carcinoma

ERBB2 amplification

HER2 overexpression may confer therapeutic vulnerability

Lung adenocarcinoma

EML4::ALK fusion

Constitutive ALK kinase is a therapeutic target

Slide 59 · Case: An EGFR-driven lung adenocarcinoma

Hypothetical teaching case

Hypothetical lung adenocarcinoma carries an activating ERBB1 mutation.

Predict persistent kinase signaling even without an external EGFR ligand.

EGFR inhibition may suppress both proliferation and survival; Resistance can later emerge.

What makes the receptor oncogenic?

Constitutive tyrosine kinase activation caused by an ERBB1 mutation.

Slide 60 · Case: A HER2-amplified breast carcinoma

Hypothetical teaching case

Hypothetical breast carcinoma demonstrates ERBB2 amplification.

Gene amplification increases HER2 abundance and oncogenic signaling.

HER2-directed inhibition is mechanistically appropriate for the illustrated lesion.

Which genetic route is present?

Copy-number amplification, rather than the ERBB1 point-mutation example.

Slide 61 · Case: An ALK fusion in lung adenocarcinoma

Hypothetical teaching case

Hypothetical lung adenocarcinoma harbors EML4::ALK.

The rearrangement produces a chimeric protein with constitutive ALK kinase activity.

This is mechanistically different from ordinary ligand-driven receptor dimerization.

What is the oncogenic protein?

A constitutively active EML4–ALK fusion kinase.

Slide 62 · Classify the receptor oncogene mechanism

Alteration

Molecular event

Most direct result

ERBB1 activating mutation

Point mutation

Ligand-independent EGFR kinase

ERBB2 amplification

Increased copy number

HER2 overexpression / activity

EML4::ALK fusion

Gene rearrangement

Constitutive chimeric ALK kinase

MET amplification on therapy

Bypass resistance

Reactivated downstream signaling

Slide 63 · A mechanistic approach to receptor-driven neoplasia

Identify the receptor gene and its specific alteration.

Infer how the lesion changes kinase regulation.

Link the resulting signal to proliferation, survival, and possible treatment dependence.

Receptor lesion

Constitutive activity

Growth / survival

Targeted response

Slide 64 · Core synthesis: Oncogenic RTKs

Normal RTKs transmit transient ligand-triggered signals by dimerization and tyrosine phosphorylation.

Point mutations, amplification, and rearrangements can create persistent receptor-kinase activity.

EGFR, HER2, and ALK illustrate lesion-specific tumor associations and therapeutic vulnerabilities.

Resistant subclones can escape via target mutation or alternative kinase activation.

Slide 65 · Source and teaching references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 7, Neoplasia, pp. 252–254.

Growth Factor Receptors: textbook narrative and Table 7.5 (source transcript in supplied project files).

Limited contextual material: Oncoproteins and Cell Growth; Growth Factors; and the opening of Downstream Components of the RTK Signaling Pathway.

All pathway figures in this lecture are original editable schematics, not reproduced textbook figures.