Dysplastic nevi cause

neighbouring keratinocytes to secrete growth factors that permanently stimulate

melanocyte division

Some

dysplastic nevi contain melanocytes with early oncogenic mutations that can

accumulate additional changes and progress to melanoma

Dysplastic nevi

prevent DNA repair pathways from functioning in surrounding skin cells

Dysplastic nevi

increase UV absorption in the skin, which directly converts normal melanocytes

into melanoma cells

Increased

expression of cell surface growth factor receptors driven by gene copy number

gain or enhanced transcription

Strengthening of

intercellular adhesion through elevated cadherin expression, reinforcing growth

inhibition

Loss of telomere

maintenance capacity, resulting in early replicative arrest

Global enhancement of

transcriptional machinery without selective activation of growth

Immune cell

infiltration into the tumour

Recruitment of

cancer-associated fibroblasts to the tumour microenvironment

Migration and

invasion into of the tumour into surrounding tissues

Tumour

growth beyond ~2 mm in diameter, due to insufficient nutrient and oxygen

delivery

Acquisition of

invasive traits has allowed the cells to outcompete surrounding tissue

Early

genetic changes have triggered sustained growth signalling without additional

heritable alterations

Accumulation of

widespread genomic instability has enabled rapid evolutionary diversification

Epigenetic

reprogramming has irreversibly altered cell identity

PD-1 antibodies increase

regulatory T cell suppression in the tumour microenvironment, enhancing effector

T cell activity

PD-1 antibodies decrease

T cell receptor specificity for antigen, indirectly enhancing downstream

PI3K/mTOR and MAPK signalling

PD-1

blockade reduces inhibitory signalling in T cells, allowing activation of

PI3K/mTOR and RAS/MAPK pathways, restoring cytotoxic function

PD-1 antibodies

inhibit oncogenic RAS/MAPK signalling in tumour cells, slowing tumour growth

Antibody triggers

complement activation, leading to lysis of tumour cells

Antibody-bound

tumour cells engage Fc gamma receptors on innate immune cells, inducing

targeted cytotoxicity

Antibody activates

death receptors on tumour cells independently of immune cells

Antibody blocks

tumour cell growth factor signalling, indirectly causing apoptosis

Cells overexpress

efflux pumps that remove trastuzumab from the extracellular environment

Truncation

of the HER2 extracellular domain prevents trastuzumab binding, allowing

continuous signalling

Antibody-dependent

cell-mediated cytotoxicity kills immune cells instead of tumour cells

Loss-of-function PI3K

mutations reduce signalling, protecting cells from antibody effects

If

a cancer cell is insensitive to one agent, it can still be targeted and killed

by the second agent

Using two drugs

allows lower doses of each, reducing side effects

The two drugs are

designed to activate two separate phases of the cell cycle

One drug primes the

cancer cell for apoptosis, and the second drug triggers cell death

Reversion of the PTCH

mutation back to wild-type

Acquisition

of a mutation in Smoothened that prevents inhibitor activity

Inactivation of an

alternative receptor tyrosine kinase pathway, such as EGFR

Increased expression

of multidrug efflux pumps that enhance intracellular inhibitor concentration

Persistent

Gli activation drives uncontrolled proliferation in neural progenitors and

basal epidermal cells

Gli target genes are

only transiently activated due to partial negative feedback by GLI3 repressor,

limiting tissue overgrowth

Constitutive SMO

activation leads to developmental arrest due to accumulation of non-functional

Gli proteins

PTCH upregulation

compensates for SMO activation, preventing tumour formation